Three common conditions cause an increase in CEP:

• Anaphylactic shock (e.g. penicillin allergy) results in increased leakage of fluid leading to sudden hypovolaemia along with peripheral oedema and bronchoconstriction The initial treatment for a patient without venous access is i.m. adrenaline (0.5 to 1 mg i.e. 0.5 to 1 ml. of a 1:1000 solution) or in a patient with i.v. access, 1 to 2 ml. boluses of i.v. adrenaline (1mg in 10 ml. or 1:10,000). Fluids and oxygen therapy should be used in addition.
  
  
• Burn injury causes a systemic 'capillary leak' which is proportional to the percentage of the burned area. The amount of fluid leakage is massive and is equivalent to 4 ml. of Ringer's Lactate per kg. per % area burn in 24 hours (Parkland formula). E.g. in a 60 kg patient with a 40% burn this requires 4 * 60 * 40 = 9600 ml, 50% given in the first 8 hours, 25% in the next two 8 hour periods) calculated from the time of the burn injury.
  
  
• Septic shock or systemic inflammatory response syndrome (SIRS) also leads to loss of CV and this fluid must be replaced in large quantities to maintain CV, despite the inevitable oedema that this causes.

Regulation of blood volume

Day to day homeostasis

The factors mentioned above are all designed to maintain the integrity of the PV and CV so that it can form the medium to allow transport of oxygen and nutrients for cellular metabolism. This ensures optimal organ function, but in a dynamic process the volumes are not static. Adequate clearance of waste products of metabolism require the kidney to excrete about 1500 ml of urine per day containing about 400-800 mmol of urea, 50 to 100 mmol K+ and 70 to 140 mmol. Na+ (depending on intake). Additional fluid losses are incurred from evaporation, respiratory tract and faeces. The total loss of fluid is about 2500 ml. water plus about 70 mmol Na+ and K+ in a 70 kg adult per day. This has to be replaced to maintain TBW. The extent of maintenance fluid requirements is more closely related to body surface area (BSA) than weight. Since a new born baby of 3.5 kg. has about 2 1/2 times the BSA/wt ratio of an adult (1/20th the weight and 1/8 th the BSA) it consequently needs 2 1/2 times the maintenance fluid per unit weight. A common formula used is shown in Table 2.

Table 2 Maintenance fluid requirements

Normally this fluid requirement is regulated both by changes in volume and osmolality in the PV being detected in the hypothalamus. An increase (due to fluid deprivation) stimulates anti-diuretic hormone (ADH) release from the supra optic nucleus which causes thirst and reduces urine output by increasing reabsorption of water from the collecting ducts in the kidney. A decrease in renal perfusion (due to fluid deprivation) increases renin output from the juxtaglomerular apparatus leads to the formation of angiotensin II (AT II). This causes thirst, constricts the efferent glomerular artery to maintain glomerular arterial pressure and filtration and also causes release of aldosterone from the adrenal cortex. The latter increases renal Na+ retention in exchange for K+ in the distal tubule.

All these changes are increased by activation of the sympathetic nervous system (SNS). If fluid deprivation becomes greater or there are abnormal losses such as diarrhoea, vomiting, ileus or haemorrhage, these processes are amplified. It is important to note that volume is usually maintained at the expense of a reduction in osmolality due to hyponatraemia. This is due to the more powerful effect of ADH over aldosterone. As plasma Na+ concentration falls, proximal tubular reabsorption of Na+ (and water) becomes intense, limiting the ability of the kidney to produce dilute urine. Administration of hyponatraemic solutions in the postoperative period in the presence of a low serum Na+ further compounds the problem. 5% glucose and 4% glucose 0.18% saline should never be given if the plasma Na+ is low. 0.9% sodium chloride or Lactated Ringer's solution (Hartmann's) is more appropriate.

Acute changes in homeostasis

Acute surgical or traumatic hypovolaemia cannot be compensated for by the more chronic processes mentioned above. Additional mechanisms are brought into play. Acute reduction in CV reduces venous return and cardiac preload so cardiac output and blood pressure (BP) fall. Reduction in BP reduces the afferent activity of the carotid sinus baroreceptors to the 'pressor' area in the dorsal hypothalamus, and results in increased SNS discharge. Reduction in venous return leads to a decrease in atrial natriuretic peptide (ANP) production (thus reducing urinary sodium loss) and a fall in output from the low pressure baroreceptors in the atria and great veins to the 'depressor' centre. The resultant fall in parasympathetic nervous system (PNS) discharge augments the action of the SNS.

The effects of this are summarised as follows:

• Direct neural effects via alpha and beta receptors.
  
  
• Catecholamine release from the adrenal medulla. In different shock states, and at different stages of shock, noradrenaline or adrenaline predominates.
  
  
• Renin release from the juxtaglomerular apparatus of the kidney (vide infra).
  
  
• Increased Na+ reabsorption in the distal tubule
  
  
• Decreased Na+ loss due to a reduction in atrial natriuretic peptide
  
  
• Vascular redistribution of blood in the kidney from cortex to medulla, the latter being the major site of Na+ and water reabsorption

The ISF compartment has an important role in maintaining circulating volume. Sympathetic stimulation, particularly to the skin and splanchnic circulation, results in a reduction of flow to these nonessential areas, by alpha adrenergically mediated arteriolar vasoconstriction. This results in a reduction of flow to the capillary beds by neuro-humorally mediated increase in the pre-capillary sphincter (PCS) tone. The hydrostatic pressure in the capillary beds falls, thus allowing fluid to enter the capillary circulation distal to the PCS as a result of the change in hydrostatic/oncotic pressure gradient (see Starling's equation above).

Intravenous perioperative fluid replacement therapy

Initially, it is pertinent to consider the types of fluids that are available and their uses. Fluids can be conveniently classified into crystalloids, colloids and blood (and blood products).

Crystalloids

These are solutions containing water and electrolytes and/or glucose made up in a concentration that is usually isotonic with plasma. This means that they contain the same number of osmotically active particles as plasma, i.e. about 300 (range 280 to 310) mosmol.l-1 of solute. Several solutions are available, 5% glucose, 4% glucose 0.18% saline, Normal (0.9%) saline and Lactated Ringer's (Hartmann's) … see table 3).

How do we make an isotonic solution? From first principles, if 1 gram molecular weight of solute is placed in a flask containing 1 kg. of solvent (i.e. 1 litre of water) it will form a molar solution. Thus, 180g of glucose (180 = the m.w. of glucose) in a kg. of water will have 1 mol. or 1000 mmols.l-1. By definition, if one mole of glucose is dissolved in 22.4 litres of solution at NTP (i.e. 0 deg C) it will exert an osmotic pressure of one atmosphere (100 kPa or 760 mm Hg). Thus, a molar solution will exert an osmotic pressure of 22.4 atmospheres (2200 kPa or 15200 mm Hg) at NTP or 25.4 atmospheres (2540 kPa or 19340 mm Hg) at 37 deg C. This amount is referred to as 1 osmol or 1000 mosmol. One mosmol at 37 deg C thus generates an osmotic pressure of 2.5 kPa (19 mmHg), thus in total the osmotic pressure of plasma is equal to 300 * 2.5 = 750 kPa (5700 mmHg). Thus, this molar solution of 18% glucose (180g per litre or 18 g per 100 ml) is hypertonic (1000 versus 300 mosmol.l-1). Each g per litre therefore gives about 5.5 mosmol.l-1, so 50g (5% solution of glucose) will produce an isotonic solution of 50 times 5.5 or 275 mosmol.l-1.

With an electrolyte such as sodium chloride, the molar solution (58.5 g of sodium chloride) will contain nearly 2000 mosmol. l-1 as in solution it is almost completely dissociated into sodium and chloride ions. Thus, roughly 1/6th. of 58.5g.l-1 is required, i.e. 9g per litre (0.9 g.100 ml-1 or 0.9% saline) with 150 mmol. of Na+ and 150 mmol. of Cl-. In a similar manner, 4% glucose and 0.18% NaCl will give 30 mosmol. of both Na+ and Cl- per litre plus 220 mosmol.l-1 from glucose making 280 in all. It can be seen that normal (0.9%) saline is hardly physiological as it contains excess Na+ (150 vs 135) and excess Cl- (150 vs 105). Excess Cl- administration can result in retention of H+ and urinary loss of HCO3- and a dilutional acidosis if administered in excess. Thus, ideally, a 'balanced' salt solution (BSS) should be used. Such a solution is Lactated Ringer's (Hartmann's solution). This contains in mmol.l-1, Na+ 130, K+3.5, Cl 105, Ca 2, Lactate 29. The latter is a H+ acceptor and is metabolised by the liver with net formation of one molecule of HCO3- and one molecule of pyruvate which can be utilised as an energy source in the Krebs cycle. It does not cause a dilutional or lactic acidosis provided that liver perfusion is adequate.

It is worth noting that a fall in serum Na+ of 5 mmol.l-1 (accompanied by a change in Cl- of the same amount) will result in a pressure dysequilibrium between the PV, ISF and ICF of 1/30th (10/300) of total plasma osmotic pressure or about 190 mm Hg (1/30th of 5900). This large pressure difference, should it occur rapidly, results in water leaving the PV into the ISF and then into the ICF in an attempt to restore osmotic balance between the fluid compartments. If this occurs acutely, as in excess absorption of non-sodium containing irrigation fluid during transurethral resection of prostate (TURP), cerebral oedema and raised intracranial pressure may occur. The latter occurs in the TURP syndrome. However, it should be noted that glycine 1.5%, the irrigation fluid traditionally used during TURP, is hypotonic. The molecular weight of glycine is 75, so 75 g dissolved in a kg. of solvent (i.e. a litre of water) would be a molar solution and would contain 1000 mosmol.l-1. Thus 1.5% glycine (or 15 g. l-1) has an osmolality of 200 mosmol.l-1. To aid detection of excess absorption of fluid, ethanol (1%) is usually added as a marker. If a significant amount of irrigation fluid is absorbed, the ethanol component will be detectable in the breath (cf a 'breathalyzer'). The concentration of ethanol thus reflecting the extent of absorption. The addition of ethanol 1% to the 1.5% glycine affects its osmolality. The MW of ethanol is 46, thus 10 g per litre (i.e. a 1% solution) will increase osmolality by 217 thus making the total osmolality of the irrigating solution 417 i.e. hypertonic! Since this combined solution is now commonly used it may account for the diminished incidence of TURP syndrome.

Thus, absorption of irrigation solution will increase overall osmotic pressure in the PV but still result in a fall in plasma Na+. In fact, the TURP syndrome is more to do with fluid overload and the possible cerebral effects of glycine than the effect of the drop in plasma Na+. In the same way, infusion of 5% glucose will cause a fall in plasma Na+ due to a dilutional effect but osmotic pressure will remain the same as the solution is isotonic. As the glucose is metabolised (the glucose concentration in 5% glucose is about 275 mmol.l-1 whilst in plasma it is 5), the osmotic pressure in the plasma will fall and water will go into the cells. The effect on cellular overhydration will depend on the rate of administration of 5% glucose. Thus, although non-sodium containing isotonic solutions will eventually result in increased cellular water they do not do so rapidly enough in most circumstances to cause problems of dysequilibrium between the body compartments.

In chronic hyponatraemia, as in patients on diuretic therapy, there is time to restore osmotic equilibrium without major pressure differences occurring between compartments. However, use of hypertonic saline may result in too rapid correction of Na+ in the plasma will cause rapid reversal of the above process and cerebral dehydration which can be equally dangerous. Thus, it is much easier to raise Na+ concentrations rapidly than to cause a fall. The commonest cause of excess hypertonic Na+ adminstration is the use of Na+HCO3- solutions (see Table 3).

Electrolyte concentrations of commonly used crystalloid solutions are shown in the Table 3.

Table 3 Content of Crystalloid solutions

Crystalloid solutions containing isotonic concentrations of Na+ do not remain in the PV following i.v. administration. The Volume of Distribution (Vd) of these fluids is ECF and thus they only provide a short term expansion of the CV. Approximately three times the volume of estimated blood loss must be given to maintain CV. In severe blood loss, massive doses of crystalloid for resuscitation (together with blood) have been implicated in the formation of pulmonary and generalised tissue oedema due to the large volumes required for resuscitation. Although this has not been substantiated in clinical trials, many anaesthetists employ colloid containing solutions for resuscitation as lower volumes are required.

Colloids

Also known as 'plasma expanders', these solutions contain high molecular weight substances such as dextrans, gelatins and starch which exert oncotic pressure and thus retain fluid in the circulating volume as stated above. In addition, naturally occurring colloid solutions such as 5% albumin and plasma protein fraction (PPF) can be used but they are expensive and have no advantages over the other synthetic colloid solutions (Table 4).

Table 4: Commonly used colloid solutions

Intraoperative fluids

Not all patients undergoing surgery need intravenous fluid therapy. Indeed, intravenous fluid administration is not devoid of risks (air embolism, deep vein thrombosis, overloading, discomfort to the patient, infection risk and considerable cost), so it should not be undertaken lightly. There are three components to fluid therapy in the surgical patient. Firstly, as it is customary to deprive patients of fluids for at least 4 hours prior to a surgical procedure under general anaesthesia, there is an element of maintenance fluid deficit. Secondly, depending on the site and severity of the operative procedure, there will be an element of compartmental fluid shift due to tissue trauma (the so-called 'third space loss'). Thirdly, there will be the additional losses of blood and other fluids such as excessive urine output, ascites and fluid collections in the peritoneal or pleural cavities.

Maintenance fluid

The average daily requirements stated above correspond to the normal physiological losses (70 kg patient) through the urine (1.5 l), faeces (100-200 ml), perspiration (300-500 ml) and respiration (500 ml). It is not necessary to replace this loss intravenously for many minor procedures where the preoperative period of fluid deprivation has been short and it is expected that oral fluids can be commenced within hours of the procedure's termination. If maintenance fluids are required then the aim should be to replace the preoperative deficit and then provide the requirements on an hourly basis until oral fluids are tolerated. On a 24 hour basis, 4% glucose 0.18% NaCl provides a suitable solution as 2500 ml (for a 70kg patient) provides 75 mmol. Na+. On an hourly basis this equates to 100 ml. 400 ml. will compensate for the preoperative deficit and then 100 ml. thereafter (see formula above). Addition of K+ is not required for short term (less than 48 hours) therapy.

Unphysiological losses

These may arise from surgical drains, nasogastric tubes or vomiting, diarrhoea, excessive body temperature and excessive urinary output due to diuretic drugs. Losses arising from nasogastric tubes, drains and urine output can be accurately measured whilst losses due to high body or ambient temperatures can only be roughly estimated.

The measurable losses must always be replaced as accurately as possible in volume, Na+ and K+ content: note that diarrhoea has a high K+ content (20-50 mmol-1) and vomit has a high chloride content (80-100 mmol-1). Patients on thiazide diuretics or frusemide may lose 50-70 mmol of K+ per litre of urine.

Elevation of body temperature is reasonably compensated for by an increase in the normal water, Na+ and K+ intake of 15% for each degree C above the normal 37.

Third space losses

This only becomes relevant during major surgery (or trauma) where there is extensive tissue damage, e.g. major abdominal and thoracic surgery. Cellular damage results in an inability to maintain the Na+/K+ pump, so Na+ and water leak into the cells which become swollen and oedematous. The major loss of fluid, however, is from the PV into a non-exchangeable compartment of the ISF (the so-called 'third space'). This is due to alterations in the oncotic/osmotic balance between the PV and ISF, again as a result of tissue damage. In extensive surgery these losses can be considerable, although estimates which have been made of 15ml.kg-1hr-1 are now thought too high. A more reasonable figure is 5 ml.kg-1hr-1 or even less. This loss of functional extracellular fluid volume (FECV), if not replaced in adequate quantities, leads to further activation of ADH and aldosterone secretion as well as inhibition of atrial natriuretic peptide (ANP). It is not surprising that there is marked water and sodium retention with oliguria in the post operative period. This fluid should be replaced with adequate quantities of a BSS such as lactated Ringer's. Recent work has demonstrated that fluid intake during major surgery should be optimised according to the individual patient requirement by observing changes in stroke volume in response to administration of fluid boluses. To do this obviously requires the use of apparatus to measure cardiac output such as the oesophageal doppler or LiDCO devices.

Blood loss

Maintenance of adequate oxygen delivery (DO2) should be the primary aim rather than simply considering blood replacement.

DO2 = Cardiac output (l.min-1) * Arterial oxygen content

(Arterial oxygen content = SaO2/100 * Hb (g.l-1) * 1.34), ignoring the small amount dissolved in the plasma. Although the latter is not numerically important, it does form the all important interface between oxygen bound to haemoglobin and cells which require it.)

Thus, at a normal cardiac output of 5 lpm, oxygen saturation of 99% and Hb of 145 g.l-1:

DO2 = 5 * (.99 * 145 * 1.34)

= 1000 ml.min-1

In considering when blood loss should be replaced, it is pertinent to consider that a 50% fall in Hb can be compensated by a doubling of cardiac output, provided circulating volume is maintained. In addition, although similar big swings in SaO2 are rarely observed, a 15% reduction to 85% is not uncommon in the postoperative period and would have the same effect as the loss of 1 to 2 units blood. It is therefore important to maintain (or increase) cardiac output and oxygenation, as a priority, in patients experiencing blood loss. Only when blood loss is likely to result in a fall in Hb to below 80g.l-1, or when there are limitations on the ability of the patient to increase cardiac output should it be replaced. Although blood may not be required until 20% or more of the blood volume is lost (in a healthy patient) it is obviously necessary to replace the fluid component so that preload and thus cardiac output can be maintained.

Please also note that 1000 ml.min-1 of oxygen can only be delivered to the tissues if a similar amount is being delivered to the alveoli. This is normally achieved by an alveolar ventilation of 5 l.min-1 and an oxygen concentration of 21%. If oxygen demand is increased then more oxygen will have to be delivered to the alveoli. This can be achieved by increased ventilation, increased oxygen concentration (O2 supplementation) or a combination of the two.

Dehydration

This is a common situation meaning depletion of water, nearly always accompanied by Na+ depletion. Clinically, the symptoms and signs are: Thirst, dry mucosae, loss of elasticity of the skin, fall in urine output, collapsed veins, cold extremities and tachycardia. This is a common situation in the postoperative patient after major surgery. It is usually due to inadequate quantities of isotonic Na+ containing fluids being given to compensate for continuing 'third space' losses. The important findings are:

• a low urine output of < 0.5 ml.kg-1 per hour in the adult
  
  
• low plasma Na+ (e.g. 125 to 130 mmol.l-1)
  
  
• high urine osmolality (> 600 or at least 2:1 urine/plasma osmolality ratio)
  
  
• low urinary Na+ (less than 20 mmol.l-1) due to Na+ retention as a result of continuing 'third space' loss
  
  
• a low central venous pressure (CVP)
  
  
• the Hb concentration may be relatively normal due to haemoconcentration

Do not give diuretics in this situation (unless the patient is on regular diuretic therapy) as it will only exacerbate the hypovolaemia. Normal saline or Ringer's Lactate should be used for initial replacement. Begin with a 10 - 20 ml.kg-1 bolus over 5 minutes and follow this with a rate of 10 ml.kg-1 per hour monitoring the signs listed above at hourly intervals. Reduce to maintenance levels when the above signs are reversed. 4% glucose 0.18% NaCl may be used in addition if the blood Na+ concentration is higher than 140 mmol.l-1

Potassium depletion

Chronic depletion is commonly seen in the ageing hospital population who have been chronically treated with diuretics for hypertension or cardiac failure. Plasma K+ starts to fall below the normal minimum of 3.5 mmol l-1 only after 10% of total body K+ has been lost (400 mmol). A good additional indicator of depletion is a high plasma bicarbonate value (>28 mmol l-1), associated with acid urine.

Depletion of 400-600 mmol causes intracellular acidosis as hydrogen ions enter the cells to maintain ionic equilibrium. Losses should be replaced over several days with oral supplements, and the underlying cause corrected.

If the patient is unable to take oral supplements K+ must be given intravenously. It is administered as KCl, and concentrations of more than 20 mmol l-1 in Normal saline or 5% glucose cause pain and thrombosis in peripheral veins. Rapid replacement is rarely advisable. If absolutely necessary, it is given through a CVP line (preferably in the High Dependency or Intensive Care Unit, with continuous ECG monitoring and frequent plasma K+ measurements.

Water intoxication

This rarely occurs, but has dramatic consequences due to hyponatraemia. The cause is usually iatrogenic. Other causes include compulsive water drinking, transurethral resection of the prostate with excessive absorption of glycine irrigation fluid, inappropriate secretion of ADH and a few rare medical disorders.

Over prescription of intravenous 5% glucose and 4% glucose 0.18% NaCl solutions is the main iatrogenic cause. This was a not infrequent in labour wards. A fall in plasma Na+, as stated above, leads to a movement of water from the hypotonic PV into the ISF and ICF to maintain osmotic equilibrium. This expansion of ICF can lead to cerebral oedema, mental disturbances and convulsions if plasma Na+ falls rapidly. Frusemide (0.5 mg kg-1) followed by 0.9% or 1.8% NaCl intravenously is an effective treatment of this emergency; a urinary catheter is needed. The speed of correction must be tailored to the speed on onset, chronic changes being corrected slowly.