Cardiac arrest may complicate the clinical course of both medical and surgical patients and the provision of prompt and efficient cardiopulmonary resuscitation is a basic skill required by all critical care personnel. The critical care unit provides an ideal environment for successful cardiopulmonary resuscitation following cardiac arrest. The rate of survival after cardiac arrest is higher in the critical care unit than in other areas of the hospital because the event is usually witnessed, the rhythm is usually ventricular fibrillation, and all the necessary personnel and equipment are immediately available. Outlook is poorest when cardiac arrest complicates renal failure, respiratory failure, or other metabolic disorders, including sepsis. Prodromal events such as hypoxaemia, arrhythmias, and electrolyte disturbances should be detected before circulatory failure occurs, and prompt intervention may prevent cardiac arrest.

Whenever possible the cause of cardiac arrest should be ascertained. It may be rapidly apparent that the serum potassium had been rising during the proceeding hours or that there had been a prodromal arrhythmia. In the postoperative cardiac surgical patient, electromechanical dissociation due to haemopericardium must always be considered. Such information and the clinical background may influence significantly the approach to resuscitation. Because the critical care unit patient is invariably undergoing ECG monitoring, ventricular fibrillation is usually recognized and treated immediately. Even in the highly advantageous environment of the critical care unit, however, a disciplined approach to basic cardiopulmonary resuscitation procedure still needs to be followed.

A resuscitation team leader should supervise the resuscitation. Ideally, this individual should have little active role in resuscitation procedures but should direct the treatment priorities, co-ordinate the participants, and assess the effectiveness of resuscitation. One team member should maintain cardiac massage while another provides ventilatory support. Another member should establish medication access, preferably by a central venous route, if not previously established, while another records interventions and medications administered.

The ABC (Airway, Breathing, Circulation) order of assessment and resuscitation should be followed. In many cases the patient will already be intubated; if not, the airway must be secured (oral airway will suffice) and ventilation provided initially by face mask and Ambu bag (self-inflating ventilation bag). Two hands are required to produce an adequate seal with an anaesthetic face mask, and another individual should provide ventilation. If the patient is already on a mechanical ventilator, ‘bagging’ the patient with 100 per cent O&sub2; will permit better synchronization with cardiac massage: slow inflations of the lungs sufficient to cause visible expansion of the chest wall are required. A major arterial pulse, such as the carotid, should be checked since a malfunctioning arterial line may not accurately reflect cardiac output.

Controversy still surrounds the use of the precordial (chest) thump. When a defibrillator is immediately to hand and when the patient is already monitored it probably has little role in the resuscitation procedure.

The ratio of cardiac compressions to each ventilated breath should be 5:1, with a compression rate of 60 to 80 per minute. Whatever cardiac compression rates are achieved, they must not interfere with effective ventilation. Recent clinical trials have not confirmed the superiority of simultaneous compression-ventilation cardiopulmonary resuscitation, as was suggested by animal studies. No more than 10 s should be permitted for any manoeuvre that demands temporary cessation of chest compression.

Assessment of the efficacy of cardiopulmonary resuscitation is difficult. An intra-arterial pressure trace is an ideal indicator of cardiac output but is not always available. End-tidal CO&sub2; greater than 2 kPa (15 mmHg) has recently been shown to indicate efficient resuscitation and favourable outcome, while an end-tidal CO&sub2; less than 1.5 kPa (10 mmHg) predicts a poor outcome. Administration of bicarbonate during resuscitation will tend to raise end-tidal CO&sub2;, misleading the clinician into believing resuscitation is more effective than it really is.

The measures that need to be applied depend upon the underlying cause of cardiac arrest. The most common arrhythmia is ventricular fibrillation which should be treated with immediate defibrillation. If defibrillation at 200 J produces no response, this should be repeated. If there is still no response, defibrillation at 360 J should be performed. If this is also unsuccessful, defibrillation at 360 J should be repeated after intravenous administration of 1 mg adrenaline (epinephrine) and then lignocaine (100 mg intravenously).

If this is still unsuccessful, alternative paddle positions (anteroposterior) or another antiarrhythmic drug should be tried. In refractory cases attempts should be made at electrical placing by either external or internal electrodes.

Cardiopulmonary resuscitation should be attempted for up to 2 min after each drug, and should not be interrupted for more than 10 s, except for defibrillation. Differentiating ‘coarse’ from ‘fine’ fibrillation has been thought to predict response to defibrillation. However, the standard approach outlined above should still be adhered to. Recent work in animal models has shown that the frequency characteristics of the pattern of ventricular fibrillation are determined by the duration of fibrillation. Such a tool, may in the future, serve to predict outcome. Once an effective cardiac output is achieved, a continuous infusion of adrenaline (epinephrine) in doses of 1 to 10 mg/h can be given to support the myocardium and circulation. In the young patient with an otherwise good prognosis, supramaximal doses may be administered. Other inotropes and pressors can be used with equal effect. Arterial blood gases and electrolytes should be monitored, and a chest radiograph obtained.

Adrenaline has largely replaced lignocaine (lidocaine) as the first pharmacological agent to be administered in cardiac arrest patients. Adrenaline, and possibly noradrenaline (norepinephrine), may increase cerebral perfusion during basic life support, although they probably do not enhance the efficacy of defibrillation. Lignocaine is effective in the treatment of ventricular tachycardia and in ventricular fibrillation prophylaxis. However, evidence to support its use in cardiopulmonary resuscitation is lacking and lignocaine may actually render the heart more refractory to electrical defibrillation.

Administration of sodium bicarbonate is no longer recommended, except where efficient ventilation can be maintained during prolonged resuscitation. After prolonged resuscitation it may be reasonable to consider administering 50 mmol of sodium bicarbonate (50 ml of 8.4 per cent) if there is persistent metabolic acidosis. Unfortunately, the buffering effect of bicarbonate results in the generation of carbon dioxide which readily diffuses into the intracellular compartment and may therefore worsen intracellular acidosis. The best way of controlling the acidosis observed during cardiopulmonary resuscitation is to establish effective ventilation and ensure an adequate circulation. Other alkalinizing agents, such as the combination of sodium carbonate and bicarbonate (Carbicarb® ), although not widely available, may offer an alternative method of correcting severe acidosis.

There is no limit to the number of defibrillations which can be attempted, assuming that the cardiac rhythm diagnosis is correct. Changing both paddle positions and the defibrillator itself should be considered, together with administration of other antiarrhythmic drugs such as bretilium.

Electromechanical dissociation is the presence of QRS complexes without apparent ventricular contractions, as evidenced by a palpable pulse or arterial pressure waves. Caution should always be exercised when using an arterial line to obtain an index of cardiac contractility, since such a device may give false information. If in doubt, the carotid or femoral pulse should be checked. Electromechanical dissociation is managed in the same way as any cardiac arrest situation except that intravenous adrenaline (1 mg) should be administered immediately.

It is essential to exclude and correct hypovolaemia, which may be disguised by pressor administration or may form part of sepsis syndrome. Pneumothorax/haemothorax should be considered in all trauma victims, while cardiac tamponade may complicate postoperative cardiac cases. Pulmonary embolism must always be considered in the postoperative patient.

Treatable electromechanical dissociation must be managed aggressively. In many cases cardiac arrest is unheralded but in retrospect it may be apparent that physiological changes were present, indicative of events such as cardiac tamponade or pneumothorax. Acute and severe blood loss will eventually result in electromechanical dissociation: volume resuscitation requires insertion of several large bore cannulae for the transfusion of blood and blood products. In patients likely to survive, emergency thoracotomy, internal cardiac massage, and cross-clamping of the descending aorta may all be required before an effective cardiac output can be achieved.

Any patient maintained on intermittent positive pressure ventilation who manifests increasing airway pressures may be developing a pneumothorax. There may be insufficient time to obtain a chest radiograph, and tube thoracostomy (possibly bilateral) may have to be performed immediately. Tamponade may develop following cardiac surgery, and the clinician must be alert to the implications of a falling cardiac output and oliguria in the face of a rising central venous pressure. The decision to reopen a sternotomy wound is never made lightly, but prompt intervention may be the only way of saving the patient who is developing tamponade. Cardiac massage in this situation is probably ineffectual at best and at worst may disrupt coronary artery vein grafts.

Asystole has grave prognostic implications, since treatment is much less effective than is the case for ventricular fibrillation. It is critical that errors in identifying asystole are excluded. Faulty equipment or very fine ventricular fibrillation may lead to the incorrect assumption that asystole is present. If any doubt exists the patient should be treated as for ventricular fibrillation.

Adrenaline, 1 mg followed by atropine 2 mg, should be administered through a central venous line. Isoprenaline (isoproterenol) may be administered if these first two agents fail to re-establish ventricular fibrillation or another rhythm. As with refractory ventricular fibrillation, persistent asystole may respond to either external or internal electrical pacing. There are few, if any, indications for the intracardiac administration of medication: the risk of myocardial damage is high and the benefits questionable.

A final indicator of the success or failure of cardiopulmonary resuscitation is the subsequent level of cerebral function. Many of the factors determining the development of neurological sequelae are self-evident, such as the duration of circulatory standstill. Other factors, such as the rapidity with which circulatory and metabolic homeostasis can be achieved, also have a significant bearing on neurological outcome. Aspects of cerebral resuscitation are considered further elsewhere.

Circulatory failure not due to cardiac arrest can be divided broadly into hypovolaemic, cardiogenic, and distributive types. Because of the hypotension and tachycardia associated with these forms of circulatory failure they are often referred to as shock syndromes. The causes of these three types of circulatory failure are summarized in Table 1 40.

The clinical response to intravascular volume depletion varies considerably, depending upon the rapidity of depletion and the peripheral vasoconstrictor responses. The classic clinical picture includes orthostatic hypotension, tachycardia, pallor, tachypnoea, cold vasoconstricted peripheries, oliguria, and mental obtundation. Minor volume depletion may be unmasked by the inadvertent administration of a vasodilator such as glyceryl trinitrate or the commencement of positive pressure ventilation. Prolonged periods of hypovolaemic shock result in permanent tissue injury developing either during the period of hypoperfusion or during subsequent reperfusion).

Clinical evaluation of the degree of hypovolaemia precedes any attempts to establish invasive monitoring. The blood pressure, degree of orthostasis, tachycardia, sweating, and peripheral vasoconstriction, together with signs of end-organ hypoperfusion such as neurological obtundation and cardiac arrhythmias will impress on the clinician the urgency of therapy. A simple clinical classification of the degree of hypovolaemia is shown in Table 2 41 and provides a guide to the blood volume deficit. Transfusion must be commenced via large bore (14 gauge), peripheral intravenous cannuli before time-consuming attempts to establish central venous pressure and arterial lines are made.

Venous access is of prime importance. Small peripheral venous and triple lumen central lines are generally inadequate for rapid, large volume transfusions. Several large peripheral lines combined with a large bore (8 or 8.5 Fr) central line will usually suffice. If a peripheral cut down is required, the insertion of the cut end of a sterile giving set (without the connector) directly into a vein ensures rapid transfusion.

The patient should be placed in the ‘feet up–head down posture’, and given oxygen supplementation. In extremis, with profound hypotension and a cardiac arrest situation developing, adrenaline (epinephrine) in 1 mg boluses should be considered. In trauma patients, whose injuries may be associated with uncontrollable blood loss, no rate or volume of transfusion will save the patient's life unless emergency surgery is undertaken.

An arterial and central venous pressure monitoring line greatly facilitates assessment of resuscitation. Correction of blood pressure, resolution of tachycardia, and an increase in central venous pressure (approaching 10–12 mmHg, relative to the right atrium) indicate satisfactory volume expansion; warming of the skin, absence of orthostatic hypotension, urine production of 0.5 to 1 ml/kg.h, and resolution of metabolic acidosis indicate re-establishment of organ perfusion.

When undertaking fluid resuscitation the clinician must first address the issue of what fluid and how much? Although there is controversy regarding the selection of crystalloid versus colloid, some rationalization can be applied on a case by case basis. The supporters of crystalloid fluids point out that hypovolaemia affects both the intravascular and interstitial spaces and that crystalloids are distributed readily to both spaces in a ratio of 1:3. The proponents of colloidal solutions emphasize the urgency of expanding the intravascular space to defend the circulation. Some agents, such as the hydroxyethyl starches, produce a volume expansion greater than the transfused volume due to their osmotic properties. Obviously, patients with slowly developing hypovolaemia secondary to long-standing gastroenterological losses, and who may be haemoconcentrated will benefit from balanced electrolyte replenishment. The massively bleeding trauma patient could be initially and briefly supported with any fluid. Very soon, however, haemodilution effects and coagulation defects will mandate blood and blood product replacement. Clearly, it is the volume and speed of replacement that determines outcome more than the initial selection of the type of fluid.

When massive transfusion is required, blood should always be warmed and replacement of clotting factors considered on a continual basis. The difficulty of achieving a balance between undertransfusion and overtransfusion should not be underestimated, even with all appropriate monitoring facilities. Remember that prolonged hypoperfusion carries the risk of organ tissue damage, while fluid overload, although not well tolerated in the elderly, can be reversed with diuretics or haemofiltration.

The initial clinical evaluation of cardiogenic failure should determine the nature of the failure (systolic versus diastolic), the underlying cause and the severity of the problem. A full clinical history and physical examination should be performed to detect ischaemic heart disease, hypertension, alcoholism, viral syndrome, valvular heart disease, or congenital heart disease. A 12-lead ECG should be obtained to identify acute myocardial infarction, left ventricular hypertrophy, heart block, or arrhythmias. Chest radiography is required for the assessment of heart size and pulmonary vascular markings, and pleural effusion.

If the patient is suffering from acute pulmonary oedema or cardiogenic shock, treatment should begin immediately. If there is less urgency an echocardiogram provides information about the size, thickness, and performance of the heart. The Doppler mode provides unique, non-invasive assessment of valvular function and allows for detection of intracardiac shunts.

The treatment of cardiogenic failure is based upon the manipulation of myocardial contractility, cardiac preload and afterload. This is achieved by the administration of inotropes, fluids, diuretics, and vasodilators, alone or in combination. The success or failure of therapy should be measured against clear therapeutic endpoints, such as a doubling of cardiac output, or a 25 per cent fall in pulmonary artery wedge pressure. The electrocardiogram, systemic arterial pressure, cardiac output, and pulmonary artery wedge pressure should be carefully monitored throughout the period of therapy. An arterial cannula is essential for monitoring patients receiving vasodilator or inotropic therapy, particularly when the blood pressure is labile. Flow-directed pulmonary artery catheters are most useful when there is uncertainty regarding left ventricular filling pressure or cardiac output.

Preload is best represented by the ventricular end-diastolic volume although clinically it is more convenient to use ventricular end-diastolic pressure. The end-diastolic pressure is, in turn, approximated by the atrial pressures; right atrial pressure for the right ventricle and pulmonary artery wedge pressure for the left ventricle. Increases in preload are associated with increases in both the extent and velocity of muscle fibre shortening, which combine to produce an increase in stroke volume. Heart failure is characterized by a limited increase in left ventricular stroke work for a given rise in left ventricular end-diastolic pressure (Fig. 1) 54.

The relationship between end-diastolic pressure stroke and volume is non-linear, and in the failing heart contractility is less responsive to increases in end-diastolic pressure. Nevertheless, alterations in preload are important determinants of cardiac performance in both normal and failing hearts. The response of heart muscle to changes in preload produces a functional reserve capable of improving cardiac output. A simple method of confirming the relationship of ventricular end-diastolic volume and ventricular end-diastolic pressure involves the use of a rapid fluid challenge. A significant and persistent rise in end-diastolic pressure following fluid challenge without an increase in cardiac output suggests that further fluid loading may be ill advised. Conversely, improved systemic arterial pressure and urine output without much change in end-diastolic pressure suggests that further fluid loading may be beneficial. A summary of factors that alter preload is shown in Table 3 42.

Any attempts to modulate preload require continuous and accurate measurement of central venous pressure and pulmonary artery wedge pressure. Central venous pressure should be transduced and displayed on the bedside monitor: it is difficult to estimate this with confidence using water manometry. Pressure should be measured at the peak of the ‘a’ wave (if in sinus rhythm) and at end-expiration. Electronic ‘mean’ venous pressures may overestimate central venous pressure in mechanically ventilated patients and underestimate pressure in those breathing spontaneously. Since the venous pressure is such a critical parameter it should be measured by the clinical attendant at the time and not taken from the previously documented clinical record.

Afterload reflects the stress distributed within the ventricular wall during ventricular ejection and is determined by impedance factors opposing ventricular ejection and by ventricular wall tension. Wall tension in turn is determined by the La Place relationship between ventricular cavity radius and pressure. Thus, afterload is not constant during ventricular ejection, but decreases as ventricular volume diminishes. In the normal heart, increases in afterload, such as an elevation in blood pressure or systemic vascular resistance, lead to a compensatory increase in preload to maintain the stroke volume.

The forces resisting left ventricular ejection can be referred to as impedance: these include the resistance of the small arteries and arterioles, the compliance and inertia of the large arteries, the viscosity of blood, and the inertia of the blood itself. Impedance (systemic vascular resistance and pulmonary vascular resistance) is the peripheral component of afterload. Vasoconstriction (or polycythaemia) therefore results in increased impedance and increased afterload. Recognizing the factors that contribute to afterload helps identify avenues of intervention that can support the heart during periods of circulatory failure (Table 4) 43.

Although few therapeutic situations require an increase in afterload, one such situation arises during conditions of isolated right ventricular failure, as might occur following myocardial infarction. Left ventricular preload is low because of impaired right ventricular output. Any factor reducing left ventricular afterload, such as volume depletion, vasodilators, or epidural anaesthetics, may preferentially reduce right heart coronary perfusion by reducing systolic pressure. Right ventricular function then becomes further impaired. If right ventricular dilatation then occurs the displacement of the interventricular septum further reduces left ventricular ejection. Left ventricular function will not improve until left ventricular afterload is increased by the administration of a systemic vasoconstrictor to improve right ventricular coronary blood flow.

Therapeutic benefit is more commonly derived by reducing afterload in cardiac failure. This is usually achieved by the administration of vasodilators to reduce impedance. Such drugs may have difference effects on arterial resistance, arterial compliance, and left ventricular volume. The greatest benefit will be seen in hypertensive patients, but significant effect can still be obtained in normotensive patients with heart failure in whom systolic arterial pressure exceeds 90 mmHg. Several agents are available, including sodium nitroprusside, glyceryl trinitrate, hydralazine, and the angiotensin converting enzyme inhibitors. In addition to the use of pharmacological agents, aortic impedance can be minimized by avoiding polycythaemia and maintaining a haemoglobin concentration of between 9 and 11 g/dl. The intra-aortic counterpulsation balloon pump is also effective in reducing aortic impedance and has the advantage of maintaining coronary filling pressure.

Nitroprusside is a vasodilator that acts directly on both arteriolar and venous smooth muscle. At least part of its action may be related to inhibition of platelet aggregation and thromboxane A&sub2; synthesis, together with it synergism with prostacyclin. It exerts its effects directly on vascular smooth muscle rather than through a receptor system and, by reducing systemic vascular resistance, it reduces myocardial oxygen consumption and improves myocardial function. Nitroprusside has been shown to be a direct dilator of vessels within the substance of the myocardium resulting in increased coronary blood flow and markedly decreasing coronary vascular resistance. Venodilation causes some reduction in preload by increasing the capacity of the venous bed. This in turn may be useful in decreasing pulmonary congestion. A theoretical concern regarding the use of nitroprusside in patients with myocardial ischaemia is that the drug might cause preferential shunting of flow into non-ischaemic areas (the coronary steal phenomenon).

Nitroprusside dilates the cerebral circulation as well as other vascular beds. This is potentially dangerous in patients with pre-existing intracranial hypertension, and may indicate a need for intracranial pressure monitoring. Nitroprusside does not impair normal cerebral autoregulation.

Nitroprusside dilates the pulmonary circulation. By blocking hypoxic vasoconstriction it may reduce arterial oxygenation in 10 to 20 per cent of patients due to increased pulmonary venous admixture.

Nitroprusside is an iron co-ordination complex which is metabolized in the blood to cyanide and then to thiocyanate (via rhodanese) and excreted in the urine. The thiocyanate metabolite itself has a mild hypotensive effect which is dose dependent and does not appear to plateau. Hypotension is generally reversed within 5 to 10 min of stopping infusion of the drug.

Nitroprusside is indicated in the treatment of congestive heart failure, in acute myocardial infarction, aortic insufficiency, acute mitral insufficiency due to papillary muscle dysfunction, or ischaemic ventricular septal defect. It should be avoided in patients with mitral or aortic stenosis. Nitroprusside is particularly appropriate therapy for hypertensive patients with acute myocardial infarction and persistent chest pain or left ventricular failure, and for normotensive patients with severe pump failure. The drug should be avoided in hypotensive patients, although it can be successfully used in conjunction with inotropic agents or intra-aortic balloon counterpulsation. Pulmonary artery catheter monitoring is generally required. Nitroprusside is particularly suitable for the treatment of hypertensive crises. In view of this propensity to induce excessive hypotension, an arterial line is generally considered to be an essential prerequisite of nitroprusside therapy. Almost all hypertensive patients will respond, although nitroprusside resistance has been described in patients with severe hypertension and renal failure. An additive hypotensive effect is seen with other drugs and it is generally wise to institute other antihypertensive therapy as soon as the blood pressure is controlled.

Generally, only modest doses of nitroprusside are needed: an initial infusion of 10 to 15 &mgr;g/min can be increased by 10 &mgr;g/min every 5 to 15 min. Most patients with heart failure show a positive response to 70 to 140 &mgr;g/min (1–2 &mgr;g/kg.min). In patients with pulmonary oedema accompanying congestive heart failure, nitroprusside is also started at a dose of 10 to 15 &mgr;g/min, but the dose is more rapidly increased (20 &mgr;g/min increments every 3–5 min) in order rapidly to reduce filling pressure and relieve symptoms. During infusion, the pulmonary artery wedge pressure should not be allowed to fall below 15 mmHg and the mean arterial pressure should be maintained at 70 mmHg (diastolic BP >50 mmHg). Initial doses of 0.5 to 1 &mgr;g/kg.min are generally effective in the treatment of hypertensive crises.

A positive response to nitroprusside infusion consists of either a drop in the pulmonary artery wedge pressure or an increase in cardiac output (or both). A decrease of 20 to 50 per cent in pulmonary artery wedge pressure and an increase in cardiac output of 20 to 40 per cent are considered positive responses. If blood pressure falls without an improvement in cardiac output or a decrease in pulmonary artery wedge pressure, nitroprusside should be discontinued or an inotrope added.

The dose required to produce a given hypotensive effect in patients with hypertensive crisis is variable, but the maximum recommended dose is about 8 &mgr;g/kg.min. Since the drug deteriorates in the light, the administration set should be opaque or covered in aluminium foil. Once diluted nitroprusside remains stable for about 24 h under such conditions. Longer term medications can be substituted once blood pressure control is obtained with nitroprusside.

Since nitroprusside is metabolized to thiocyanate, excessive amounts administered over long periods to patients with severely compromised renal function can result in the accumulation of thiocyanate. Side-effects include nausea, vomiting, hiccups, mental confusion, and psychotic behaviour. The clinical manifestations of thiocyanate toxicity are lactic acidosis, confusion, hyper-reflexia, convulsions, tinnitus, and blurred vision. Infusion rates below 3 &mgr;g/kg.min for less than 72 h are not usually associated with toxicity. Monitoring blood thiocyanate levels may be necessary in patients requiring infusions for longer than 2 to 3 days: thiocyanate levels below 10 mg/dl are considered satisfactory.

Nitrates cause direct relaxation of vascular smooth muscle. Their predominant effect is on the capacitance vessels (veins), although arterioles are also dilated at higher doses. Nitrates may act on smooth muscle by releasing prostacyclin from vessel endothelial cells. Both glycerine trinitrate and nitroprusside exert a similar effect on preload with nitroprusside causing a greater decrease in afterload.

Glycerine trinitrate has an antianginal effect, although there is controversy over the mechanism of action. Several studies suggest that its major effect is due to systemic venodilation, which reduces preload and ventricular size, and in turn decreases left ventricular end-diastolic pressure, intramyocardial wall tension, and myocardial oxygen consumption. The drug may also decrease ischaemia by promoting epicardial and collateral coronary blood flow. Within the usual dose range, glycerine trinitrate has minimal effects on arteriolar tone: blood pressure and cardiac output are rarely affected unless preload is markedly reduced or unless significant myocardial hypoxia is relieved. In the higher dose range, glycerine trinitrate acts in a similar fashion to nitroprusside, causing a fall in systemic vascular resistance, increasing cardiac output, and decreasing blood pressure.

Glycerine trinitrate is widely distributed in the body and is rapidly metabolized to dinitrates and mononitrates, with a half-life of approximately 4 min.

Because glycerine trinitrate has little direct effect on blood pressure but has a profound effect on pulmonary artery wedge pressure, it may be preferable to nitroprusside in patients without hypertension who have heart failure and pulmonary oedema. The intravenous dosage is highly variable but can be started at 10 &mgr;g/min and adjusted every 5 to 10 min until the desired haemodynamic response (drop in pulmonary artery wedge pressure) is achieved. The dose which is usually effective in patients with heart failure is 30 to 100 &mgr;g/min. If no benefit is derived at a dose of 400 to 500 &mgr;g/min, other pharmacological options should be considered. High doses of glycerine trinitrate over several days are well tolerated. Continuous infusion is titrated to produce relief of chest pain or reversal of ischaemic ECG changes. It is essential that left ventricular filling pressure is adequate, otherwise significant hypotension may ensue. Occasionally, a precipitous fall in blood pressure in response to glycerine trinitrate administration may be the first indication that a particular patient is intravascularly depleted.

Side-effects include headache, sinus tachycardia, and hypotension. Rare complications include methaemoglobinaemia, paradoxical hypertension with bradycardia, and exacerbation of hypoxaemia.

Short-acting loop diuretics are considered an essential component of the treatment of acute heart failure. Frusemide (furosemide) in doses of 10 to 100 mg should be administered intravenously to patients with increased preload. Extremely large doses of frusemide (250–4000 mg/day) have been recommended in patients with reduced renal function but are unlikely to produce a meaningful diuresis: the addition of 2.5 to 5 mg of oral metolazone to frusemide is preferred. Intravenous bumetanide, a potent and short-acting loop diuretic, in doses of 0.5 to 2 mg, may be effective in patients resistant to frusemide.

Although the optimal response to diuretic therapy is a reduction in left ventricular filling pressure and increased urine output, the response of left ventricular pump function to diuretics is variable. Loop diuretics are of great value in patients with decompensated heart failure and should be used as needed to control pulmonary congestion. In the absence of a significant and sustained diuresis in patients with renal failure short-term reliance on venodilators may buy time while alternative means such as haemofiltration are established.

The terms contractility and myocardial performance should not be confused: they are not synonymous. Myocardial performance is the sum total of preload, afterload, contractility, and heart rate, and is usually measured as cardiac output, while contractility is only one component of myocardial performance. Contractility is the final determinant of cardiac output and can be defined as the force of ejection, independent of afterload or preload. Contractility is not fixed but variable: it improves with adrenergic stimulation and increased coronary blood flow, and worsens due to the action of pharmacological and physiological depressants (barbiturates, general anaesthesia), metabolic abnormalities (hypothyroidism, sepsis), and loss of ventricular substance (myocardial infarction). Some of the factors that influence contractility are listed in Table 5 44.

The direct measurement of contractility is technically difficult since most techniques, such as ejection fraction, may be influenced by the relative state of preload or afterload at the time the measurement is made. However, it is conceptually important because it can be increased by a number of inotropic agents commonly used to treat circulatory failure. The most reliable and commonly used inotropic agents include dopamine, dobutamine, adrenaline (epinephrine), noradrenaline (norepinephrine), isoprenaline (isoproterenol), and glucagon.

Dopamine is the immediate precursor of noradrenaline in the catecholamine synthetic pathway. It has both &agr;- and &bgr;-adrenergic effects but differs from other catecholamines by producing vasodilation in renal, mesenteric, coronary, and intracerebral arterial vascular beds. This dopaminergic effect is not blocked by &bgr;-blockers. Since dopamine acts on a variety of receptors, and each receptor has a different dose–response relationship in different patients, a wide range of haemodynamic effects may be elicited under different conditions. Dopamine exerts &bgr;&sub1;-adrenergic activity, mainly by releasing noradrenaline from myocardial storage sites. It also increases contractility and heart rate by its direct action on &bgr;-adrenergic receptors, effects which are blocked by &bgr;-blockers. &agr;-Adrenergic effects causing vasoconstriction occur at high doses. In addition to its direct effect on &agr;-adrenergic receptors, dopamine may also cause contraction of vascular smooth muscle by acting on a serotonin or tryptamine-sensitive receptor.

Low doses (0.5–2 &mgr;g/kg.min) may cause minimal increase in cardiac output contactility. Its major effect is an increase in renal blood flow and urine output due to stimulation of dopaminergic receptors. The renovascular effect is probably the most commonly exploited property of dopamine, but it may be lost at infusion rates greater than 5 &mgr;g/kg.min, when there is an increase in cardiac contractility. At even higher doses (>10 &mgr;g/kg.min) the &agr;-adrenergic effects increase. Pulmonary artery and pulmonary artery wedge pressure may increase at high doses of dopamine. In addition, dopamine may increase intrapulmonary shunt fraction, resulting in a fall in oxygenation.

Dopamine selectivity increases renal and mesenteric blood flow by its action on dopaminergic receptors, but some of the renal effects of dopamine may be due to the inhibition of aldosterone secretion resulting in a natriuresis and increased urine output.

Intravenous administration of dopamine results in near steady-state levels in 5 min. The half-life of intravenously administered dopamine is approximately 1 min: it is metabolized by both catechol- O-methyl transferase and monoamine oxidase enzyme systems, and is ineffective when given orally. Dopamine is inactivated by bicarbonate and other alkaline solutions. The initial dose depends on specific aims of therapy: for the promotion of renal or splanchnic blood flow doses of 1.5 to 2.5 &mgr;g/kg.min are generally adequate, while a vasopressor effect is only achieved at doses greater than 5 &mgr;g/kg.min. Most patients show a pressor response to dopamine infusion at doses below 20 &mgr;g/kg.min, although some may require infusion rates in excess of 50 &mgr;g/kg.min. At these levels there are significant vasoconstrictor effects.

Arrhythmias are generally associated with administration of high doses of dopamine or the presence of myocardial ischaemia, metabolic acidosis, or hypoxaemia. Dopamine may increase myocardial conduction and precipitate a rapid ventricular response in patients with atrial fibrillation.

Peripheral gangrene may be seen in patients with profound shock treated for a prolonged period with large doses of dopamine. Hypotension may occur secondary to vasodilation in certain patients receiving low doses of dopamine: a specific vasopressor should be administered until an adequate blood pressure is obtained. Other side-effects include nausea, vomiting, angina pectoris, and, occasionally, hyperglycaemia. Tissue necrosis due to local extravasation is a serious complication and for this reason dopamine should be routinely administered via a central vein. If peripheral extravasation does occur, the area should be infiltrated locally with 10 ml of normal saline containing 5 to 10 mg of phentolamine.

Dopamine is metabolized by the monoamine oxidase system. and its effects are therefore greatly potentiated in patients receiving monoamine oxidase inhibitors. These effects may persist several weeks after cessation of such inhibitors. Phenothiazines, haloperidol, and tricyclic antidepressants have mild &agr;-adrenergic blocking actions which may reduce the peripheral vasoconstricting effects of dopamine. Propanolol and other &bgr;-blocking agents blunt the cardiac stimulation produced by dopamine.

Dobutamine is a synthetic catecholamine that was the product of a systematic attempt to design a pure &bgr;&sub1;-adrenergic agent. Dobutamine is structurally related to isoprenaline (isoproterenol) and acts directly on &bgr;&sub1;-adrenergic receptors in the myocardium. Unlike dopamine, dobutamine does not enhance noradrenaline release from nerve endings, nor does it act on dopamine receptors. Its action is therefore not potentiated by monoamine oxidase inhibitors. The predominant &bgr;&sub1;-receptor action increases myocardial contractility, and it has less effect on heart rate than does dopamine. Dobutamine has relatively weak &bgr;&sub2;- and &agr;-receptor activity, with peripheral vasodilation predominating. It has a short half-life (<2.5 min) in patients with heart failure: this becomes important if it is necessary to reverse an adverse effect such as ventricular tachycardia. There are no biologically active metabolites of dobutamine.

At low to moderate dose levels, dobutamine increases myocardial contractility, causes peripheral vasodilation, and augments renal blood flow. Some increase in heart rate can be expected. In addition, a decrease in pulmonary artery wedge pressure often accompanies the improved cardiac output.

Dobutamine increases cardiac output and by doing so increases intrapulmonary venous admixture. Relief of pulmonary venous congestion brought about by a reduction in pulmonary artery wedge pressure improves pulmonary compliance and reduces the work of breathing.

Dobutamine is metabolized by catechol- O-methyl transferase and glucuronide transformation in the liver, most of the drug being eliminated unchanged by the kidneys and biliary tract. Its elimination follows first-order kinetics.

Positive inotropic effects occur with doses as low as 0.5 &mgr;g/kg. min, although the usual initial dose is 2 to 2.5 &mgr;g/kg.min. Therapeutic effects of the drug usually plateau at 15 to 20 &mgr;g/kg.min. Dobutamine is useful in the treatment of cardiogenic and septic shock if the associated hypotension is not severe. If hypotension is a problem, noradrenaline (norepinephrine) or high doses of dopamine may need to be added.

Cardiac arrhythmias are the most frequent toxic side-effect, but these are less common than with dopamine or isoproterenol. Hypotension may occur, especially if preload is inadequate. Tolerance may be observed after prolonged continuous infusion, an effect that is related to down-regulation of &bgr;-receptors. Dobutamine is contraindicated in patients with obstructive cardiomyopathy since it may increase cardiac outflow obstruction. The ventricular response in atrial fibrillation may be increased.

Noradrenaline is the neurotransmitter of postganglionic sympathetic nerves and is released from the adrenal medulla. In the heart, it is synthesized and stored in granules in myocardial adrenergic nerve endings. It is a &bgr;&sub1;-agonist and has minimal effects on &bgr;&sub2;-receptors. &agr;-Adrenergic receptor effects result in marked peripheral vasoconstriction and increased left ventricular afterload.

Cardiovascular effects are not apparent with doses below 2.5 &mgr;g/min, but above that, noradrenaline increases systolic pressure proportionately more than diastolic pressure. This results in a significant increase in systemic vascular resistance and mean arterial pressure. Heart rate may be slowed by a baroreceptor reflex and cardiac output remains unchanged or slightly reduced. Noradrenaline is a potent venoconstrictor, and increases venous return by decreasing vascular capacitance. Noradrenaline increases afterload, preload, and contractility and can greatly increase myocardial work and oxygen demand. Coronary blood flow may be increased through an increase in the filling pressure gradient between the mean arterial pressure and the left ventricular end-diastolic filling pressure. Right ventricular perfusion may be greatly enhanced since the majority of right-sided coronary flow occurs during systole.

Noradrenaline may be a respiratory stimulant through its action on the carotid bodies. It has little effect on bronchial smooth muscle, but it will increase pulmonary vascular resistance: this is potentially disadvantageous in patients with underlying pulmonary hypertension.

Physiologically, noradrenaline is a potent vasoconstrictor of the renal artery bed. This effect can be ameliorated to some degree by concurrent administration of low dose dopamine. Noradrenaline produces vasoconstriction in the liver and splanchnic beds, resulting in decreased flow. However, in patients with distributive (septic) shock noradrenaline may increase renal blood flow and enhance urine production by increasing perfusion.

Noradrenaline does not vasoconstrict vessels supplying the brain, although &agr;&sub2;-adrenergic receptors are present on these vessels. The powerful pressor effects of noradrenaline may maintain cerebral perfusion during periods of circulatory collapse; indeed, noradrenaline may be as effective as adrenaline in supporting the circulation during cardiac arrest.

Noradrenaline is enzymatically degraded in the liver and kidneys. There is also reuptake at &bgr;-adrenergic and non-neuronal receptor sites.

The pressor effects of noradrenaline may be beneficial in distributive (septic) shock, where there is systemic vasodilation and peripheral hypoperfusion as evidenced by low systemic vascular resistance and lactic acidosis. Noradrenaline will support myocardial and cerebral perfusion effectively while cardiac output and oxygen delivery is carefully monitored. Although there are theoretical limits to the dose that can be safely administered, the dose can be progressively increased to achieve the desired effect. It is essential to exclude volume depletion before resorting to pressor therapy. Following calcium-channel blocker overdose, intravenous calcium and noradrenaline may quickly restore vascular tone.

Systemic vasoconstriction resulting in organ ischaemia, especially of the dermal, renal, and mesenteric vascular beds, may produce irreversible injury. These effects must be weighed against the potential benefits. Palpitations, angina, headaches, hyperglycaemia, and hypocalcaemia may follow noradrenaline administration.

Adrenaline is a naturally occurring catecholamine with &agr;-, &bgr;&sub1;-, and &bgr;&sub2;-adrenergic activity. For circulatory support it may be infused in doses of between 0.01 and 0.2 &mgr;g/kg.min. Although the oxygen supply to oxygen demand ratio may be adversely affected, adrenaline may improve peripheral perfusion. It is particularly, useful in the treatment of distributive circulatory failure, such as the sepsis syndrome and anaphylactic reactions. Although the same effects can be achieved by combinations of agents with predominantly &agr;-adrenergic effects (noradrenaline) and &bgr;-adrenergic effects (dobutamine), adrenaline still has a place in the current management of circulatory failure.

Isoprenaline (isoproterenol) has both &bgr;&sub1;- and &bgr;&sub2;-adrenergic activity, and produces peripheral vasodilation and an increase in myocardial contractility and heart rate. The tachycardia and reduced coronary perfusion pressure results in a much reduced oxygen supply to oxygen demand ratio. It is therefore not the drug of choice for use in patients with myocardial failure, but it may have application in severe bradycardias not associated with myocardial ischaemia.

Glucagon is a pancreatic polypeptide that has inotropic and chronotropic effects which are not dependent on &bgr;-receptor responsiveness. By directly stimulating adenylcyclase it increases intracellular AMP concentration. Although not a first-line drug for use in circulatory failure, it may be effective when other inotropes have failed.

Milrinone and enoximone are powerful phosphodiesterase inhibitors which may be beneficial in patients with severe heart failure who are unresponsive to dobutamine or dopamine. These agents have combined inotropic and vasodilator properties and are effective even in the presence of &bgr;-receptor down-regulation.

Dobutamine and dopamine have very different haemodynamic profiles and should not be considered to be interchangeable. Because dopamine causes substantial peripheral vasoconstriction and can increase pulmonary capillary wedge pressure, it should be used cautiously in patients with acute heart failure who have increased peripheral vascular resistance and elevated wedge pressures. Dobutamine may be preferable to dopamine for the treatment of acute congestive heart failure, while nitroprusside is preferable when the systolic pressure is above 90 mmHg. Combinations of all three drugs are commonly used. A logical regimen in a patient with severe congestive heart failure would be nitroprusside and dobutamine with infusion of low (renovascular) doses of dopamine. Recently introduced inotropic agents such as the &bgr;-adrenergic agonists amrinone and dopexamine and the phosphodiesterase inhibitors milrinone and enoximone combine inotropic and vasodilator properties (afterload reduction) and theoretically reduce the risk of increasing myocardial work.

The effects of inotropes, vasodilators, and diuretics on myocardial performance are well represented by the plot of left ventricular stroke work index and pulmonary artery wedge pressure. In the failing heart there is greatly reduced myocardial performance for a given preload. As shown in Fig. 2 55, the depressed curve of heart failure can be shifted toward normal by inotropic drugs, or vasodilator drugs.

These effects may be complementary when the drugs are infused together. Note that diuretics usually reduce filling pressure without augmenting output. An inotrope such as dobutamine may not only increase contractility but may also reduce pulmonary artery wedge pressure, while dopamine may increase pulmonary artery wedge pressure, especially at high doses.

Ultimately, oral inotropes and vasoactive agents will be needed to replace acute systemic therapy. Several effective oral agents, including diuretics, cardiac glycosides (digoxin), nitrates, hydralazine hydrochloride, and the angiotensin converting enzyme inhibitors, are available for the treatment of stable or compensated congestive failure. Of these the combination of diuretics and angiotensin converting enzyme inhibitors has had the most impact on morbidity. Patients should be supervised while a low dose of an oral agent (such as captopril 6.25 mg, or enalapril maleate 2.5 mg) is administered and the intravenous drug is gradually discontinued. Cautious dose increases are needed in order to avoid hypotension, especially if the patient is volume depleted. If the first dose of an angiotensin converting enzyme inhibitor is tolerated, doses should be increased until a maintenance dose is achieved. Since angiotensin converting enzyme inhibition tends to increase serum potassium levels, potassium supplementation should be very cautious and serum levels need to be monitored. Angiotensin converting enzyme inhibitors may also cause acute renal failure, particularly in patients with chronic azotaemia and renal artery stenosis, making it important to monitor serum creatinine and blood urea nitrogen levels.

Heart rate is an important determinant of cardiac output. Since cardiac output is determined by the product of heart rate and stroke volume, cardiac output for a given stroke volume will increase as heart rate increases. As heart rate falls, the diastolic filling interval lengthens, stroke volume increases, and cardiac output is protected. However, at very low heart rates (approaching 40 beats/min) there is insufficient stroke volume reserve to compensate for the fall in rate and blood pressure may fall. The presence of an effective atrial pump helps to prime the ventricle and, in slow supraventricular and idioventricular rhythms, bradycardia is less well tolerated. In the clinical setting it is therefore essential to determine whether bradycardias are associated with circulatory failure. If blood pressure is maintained, continued observation may be all that is required; if hypotension develops, active intervention is required. Sinus bradycardia usually responds to atropine (0.6 mg) but other rhythms may need administration of isoprenaline (isoproterenol) or electrical pacing. In the severely ill ventilated patient, who often has multiple organ system failure, sinus bradycardias may accompany tracheal suctioning, even in the absence of hypoxaemia or metabolic disturbances. Pretreatment with atropine will generally prevent these episodes. Alternatively suctioning can be performed through an airtight port attached to the swivel connector of the endotracheal tube. The explanation for such episodes is unclear but they must represent the unopposed activity of the vagal system.

The effect of tachycardia on cardiac output depends on the underlying contractile state of the myocardium, and when contractility is impaired cardiac output may fall. In this situation, cardiac output can be increased by an increase in heart rate up to approximately 110 beats/min. In the presence of heart disease, heart rates greater than 160 beats/min are badly tolerated, while in patients with healthy myocardia heart rates of up to 180 beats/min are associated with an intrinsic increase in contractility that accompanies the tachycardia. In patients with ischaemic heart disease increased heart rate seriously raises myocardial oxygen consumption. Some prosthetic cardiac valves function poorly at high cardiac rates due to the inertia of the valve mechanism and attempts should be made to keep heart rates below 120 beats/min.

Sinus tachycardia is usually a physiological response to a specific event or series of events, which may include endotoxaemia, fever, or hypovolaemia. Until the underlying cause is remedied the tachycardia will remain. Attempts to slow sinus tachycardia with myocardial depressant agents, such as &bgr;-adrenergic blockers, is not recommended.

Arrhythmias developing in patients in the intensive care unit are commonly the result of metabolic disturbances, hypovolaemia, increased afterload, or hypoxaemia. A concerted effort must be made to identify and correct these disturbances before resorting to treatment with antiarrhythmic agents. Indeed, resistance to these agents can be expected until the underlying abnormalities are corrected. Thereafter, the urgency with which arrhythmia needs to be corrected is determined by the severity of the haemodynamic disruption. Obviously, the onset of shock may necessitate emergency electrical cardioversion, while arrhythmias in the absence of haemodynamic disturbance can be managed with appropriate antiarrhythmic drugs or elective electrical cardioversion. As a general rule, ventricular arrhythmias produce greater haemodynamic disturbance than supraventricular rhythms. A summary of treatment regiments for both supraventricular and ventricular arrhythmias is shown in Fig. 3 56.

The treatment of distributive circulatory failure provides one of the most challenging aspects of critical care. Although there are several causes of distributive circulatory failure, including anaphylaxis and neurogenic shock, it is the sepsis syndrome that accounts for most cases. The pathophysiology and principles of management of the sepsis syndrome provides a model that can be applied to most forms of distributive circulatory failure irrespective of cause.

The sepsis syndrome, and associated multiple organ system failure, is the most common cause of death in critical care patients. It represents the host response to endotoxaemia caused by a wide range of micro-organisms. Sepsis syndrome is characterized by low peripheral vascular resistance which, in the presence of normal cardiac function, is coupled with increased cardiac output (high output failure) and low filling pressures. However, cardiac function, along with the function of other organ systems, may be greatly impaired. Those patients who do not generate high cardiac outputs in the face of a septic insult generally have a poor prognosis.

The definition of the sepsis syndrome is based upon the demonstration of signs of infection, shock, and evidence of organ system dysfunction as described in Table 6 45.

Sepsis syndrome is the pathophysiological responses to systemic infection or endotoxaemia. The clinical syndrome can be produced by a wide range of organisms including Gram-positive and Gram-negative bacteria, protozoa, viruses, and fungi. In a significant proportion of cases an infective organism is never isolated. Although endotoxaemia is not consistently present in early sepsis, it is usually present in late, severe sepsis syndrome with multiple organ system failure and is associated with a poor prognosis. Systemic endotoxaemia may also result from translocation of endotoxin and bacteria from the intestinal lumen into the circulation and may explain the development of sepsis syndrome in trauma and burn patients (Fig. 4) 57.

Spillover of endotoxin into the circulation is known to occur in patients with inflammatory bowel disease such as Crohn's disease and in those with obstructive jaundice. Bile salts may have a beneficial effect by binding endotoxin, and therefore their absence may predispose towards endotoxaemia. The presence of circulating micro-organisms and endotoxins appears to trigger an immunological and inflammatory cascade with complement activation and the release of a number of host-derived mediators, including tumour necrosis factor, interleukins, and myocardial depressant factor. These mediators are probably responsible for the systemic vasodilation, hypotension, and multiple organ system failure which are often seen.

The presence of multiple organ system failure is usually only too apparent to the clinician, although formal diagnostic criteria can be defined and are summarized in Table 7 46. Not surprisingly, the greater the number of organ systems involved the worse the prognosis.

Colonization of the upper gastrointestinal tract, particularly with Gram-negative organisms, may be a significant aetiologic factor in sepsis. It may also play a role in the perpetuation of the sepsis syndrome. Colonization of the stomach and upper small bowel in the critically ill patient provides a major source of endogenous infecting organisms. Colonization of the upper gastrointestinal tract is promoted by parenteral administration of antibiotics which are excreted in saliva, bile, and intestinal mucus, and which suppress the endogenous intestinal anaerobic flora. Other factors that promote colonization are listed in Table 8 47. Gastrointestinal tract colonization provides a reservoir of pathogens that not only increase the enteric endotoxin pool but also increase the risk of nosocomial lung infection developing following the aspiration of gastrointestinal contents.

Selective decontamination of the digestive tract with orally administered non-absorbable antimicrobial agents has been recommended as a method of reducing the colonization of the upper gastrointestinal tract in the critically ill patient. This reduces nosocomial lung infections, although there has not been a consistent reduction in mortality. The procedure appears to be well tolerated and resistant strains of colonizing micro-organisms do not commonly develop. Selective decontamination may, therefore, be recommended in patients with severe multiple injuries and in those in whom persistent endotoxaemia is suspected. Several ‘recipes’ have been proposed, including the combination of oral polymyxin, amphotericin, and gentamicin with a systemic &bgr;-lactam such as ceftazidime. This combination is administered as a paste for the oral cavity and as a mixture to pass through the digestive tract. Polymyxin is particularly effective in reducing faecal endotoxin levels.

Sepsis syndrome is characterized by defective oxygen utilization in the face of a high cardiac output. The reduced oxygen consumption may be associated with raised blood lactate levels, suggesting anaerobic metabolism consistent with an intracellular defect in oxygen utilization or microvascular shunting that creates areas of tissue hypoxaemia. It is probable that both elements exist and contribute to the impaired oxygen uptake by the tissues. When tissue hypoxia becomes more severe, as evidenced by a fall in venous oxygen saturation (Svo&sub2;) below 60 per cent hyperlactaemia can be expected. Tissue hypoxia, however, as evidenced by reduced Svo&sub2;, may be present even in the absence of elevated blood lactate levels. A normal or high Svo&sub2; does not exclude tissue hypoxia but merely reflects the degree of reduced tissue oxygen utilization and high output state.

In health, oxygen consumption is largely independent of delivery until oxygen delivery falls below about half the normal rate, that is, below 7 ml/kg. In the sepsis syndrome, not only is oxygen consumption reduced, but there appears to be delivery dependent oxygen consumption at all levels of delivery. This claim has been challenged on the grounds that the formulae for calculating oxygen consumption and delivery, using the Fick principle, both contain the common elements of cardiac output and the oxygen content of arterial blood, and that they are therefore inevitably correlated. Indeed, when oxygen uptake is derived from analysis of exhaled gases, no such delivery dependence of oxygen consumption is found. Irrespective of how this controversy is resolved, the underlying principles of using combinations of inotropes and vasopressors to optimize cardiac output and oxygen delivery still pertain, although it remains to be conclusively demonstrated that such methods improve survival.

Management is aimed at organ system support, the suppression or amelioration of the toxic effects of the septic process, and, most important, the identification and eradication of the septic focus. Some forms of organ system support, such as mechanical ventilation and haemofiltration, are readily achievable, while the support of the brain, circulation, and gastrointestinal tract has to be approached indirectly by trying to attain supranormal levels of oxygen delivery (Table 9) 48.

In addition to organ system support, specific interventions aim at the eradication of the septic focus or at inhibiting the inflammatory cascade. Appropriate antibiotics must be selected, but these will eventually prove ineffective unless surgical drainage of large foci of infection is undertaken.

An aggressive approach to clinical, radiographic, sonographic, and microbiological surveillance is required if the focus of infection is to be identified and eradicated. The investigations should be directed along the lines suggested by a thorough understanding of the clinical problems. Recognizing the limitations of non-invasive investigations should encourage early diagnostic laparotomy. The clinical features of intra-abdominal sepsis may be difficult to elucidate in the sedated patient receiving potent analgesics.

Many attempts have been made to interrupt the inflammatory cascade of sepsis. Cortiocosteroids appear to be ineffective, as do specific inhibitors of leukotriene and prostenoid production. With the advent of improved assays for endotoxin it has been shown that endotoxaemia predicts impending sepsis in the febrile patient and correlates with clinical events and the development of lactic acidosis. Recent experience with administration of antibody against the lipopolysaccharide component of endotoxin in patients with Gram-negative sepsis has shown a significant reduction in overall mortality, particularly in those presenting with shock. Such immunotherapy against endotoxins and cytokines may, in time, become the standard for specific intervention in sepsis.

The flow-directed pulmonary artery catheter is a multilumen tube used for the catheterization of the right-sided circulation. It incorporates a balloon, of about 1.5 ml capacity, at the tip: this facilitates the passage of the catheter into the pulmonary artery as well as allowing the determination of left-sided filling pressures. A thermistor at the tip enables the determination of cardiac output by the thermodilution technique. Newer catheters include the capacity for sequential atrioventricular pacing as well as fibreoptics for continuous monitoring of mixed venous oxygen saturation. Most recently, a pulmonary artery catheter has been introduced which incorporates a rapid response thermistor facilitating the estimation of right ventricular ejection fraction and, therefore, right ventricular end-diastolic volume.

At the proximal, hub end of flow-directed pulmonary artery catheter there are several ports and connections; a distal and proximal port, a balloon inflation port, a thermistor connection, and, in some, a fibreoptic connection.

There has been much controversy regarding the risk/benefit of the pulmonary artery catheter in both coronary care and intensive care, fuelled partially by the lack of published prospective trials. It is therefore incumbent on each clinician to determine the true need for its insertion. Indications for pulmonary artery catheterization are constantly evolving; however, current indications are summarized in Table 10 49.

The utility of data derived from pulmonary artery catheterization rests upon the fact that there are limits to the reliability and accuracy of clinical methods of determining pulmonary artery pressure, pulmonary vascular resistance, left atrial pressure, peripheral vascular resistance, and cardiac output. Several studies have revealed that even when radiographic and clinical criteria are critically evaluated the presence or absence of left ventricular failure cannot always be reliably predicted. Another test of the utility of pulmonary artery catherization is whether or not meaningful alterations in therapy result from the information derived from the flotation catheter. It has been estimated that in between one- and two-thirds of patients investigated by this means therapeutic alterations are made as a result of the information obtained.

Given the large amount of potentially valuable information obtainable from the catheter, it would be tempting to use it in most critically ill patients. However, the incidence of serious complications is high enough to mitigate against its routine use. Some of the complications related to the pulmonary artery catheter are listed in Table 11 50.

The overall incidence of complications is difficult to assess. However, many of the serious complications can be avoided by adhering to standard procedures. Checking the chest radiograph following insertion of the catheter should detect pneumothorax and over-distal placement of the catheter tip (overwedging). Furthermore by ensuring that the pulmonary artery pressure trace returns after each deflation of the balloon, lung infarction should be prevented. By adopting strict aseptic insertion techniques, using a plastic sheath around the external portion of the catheter, and by removing the catheter within 72 h the risk of sepsis and endocarditis is reduced.

Correct and skilful insertion technique cannot be learnt from a textbook but requires careful instruction by an experienced clinician. However, a few recommendations and comments can be made at this juncture. Full aseptic technique requires the wearing of surgical gown, cap, mask, and gloves, and preparation of as much of the equipment as possible before touching the patient. This includes attaching three-way taps, flushing all channels with heparinized saline, checking the integrity of the balloon, and completing in-vitro calibration of the pulmonary artery catheter oximeter (if used). The use of the internal jugular route, particularly the right internal jugular, facilitates placement. Prior insertion of a pulmonary artery catheter sheath (8–8.5 Fr) makes later replacement with either another pulmonary artery catheter or a triple lumen catheter very much more convenient. As the catheter is introduced its natural curvature should be maintained such that it will be directed through the tricuspid valve and up into the right ventricular outflow tract (with the balloon inflated). The catheter should be advanced slowly, about 2 cm every 2 s, watching its distal port pressure trace. As each heart chamber is entered (right atrial and right ventricle), the pressure should be noted. Once in the pulmonary artery the catheter should be advanced until it wedges, the pulmonary artery wedge pressure (or pulmonary artery occlusion pressure) being monitored. When the balloon is deflated the pulmonary artery trace should reappear. Subsequent inflation of the balloon should initially continue to give a pulmonary artery trace: as the catheter uncoils and advances, it will again wedge. This should be the ideal catheter position. A portable chest radiograph will confirm the catheter position. Right atrial and pulmonary artery wedge pressures should be recorded at the top of the ‘a’ wave at end-expiration.

Right atrial waveform, pulmonary artery systolic, diastolic, and mean pressures, and pulmonary artery wedge waveform should be measured. In the spontaneously breathing patient, the pulmonary artery wedge pressure reflects left atrial pressure. The relationship of pulmonary artery wedge pressure to left ventricular end-diastolic pressure is more complex however. Pulmonary artery wedge pressure provides an accurate indication of left ventricular end-diastolic pressure, provided that the latter is low and there is no mitral valve disease. At high left ventricular end-diastolic pressures (30–35 mmHg), the pulmonary artery wedge pressure is usually 5 to 10 mmHg lower. The pulmonary artery diastolic pressure is generally 1 to 2 mmHg greater than the pulmonary artery wedge and can be used as a crude index of left atrial pressure, again assuming that there is no mitral valve or pulmonary disease. The pulmonary artery wedge pressure is not usually higher than the pulmonary artery diastolic pressure and should never be greater than the mean pulmonary artery pressure. When this occurs (assuming no mitral regurgitation) the discrepancy is usually caused by overwedging of the catheter or by improper measurement of the pulmonary diastolic pressure.

This generally requires the averaging of three reasonably close, sequential measurements. Ideally, ice-cooled saline (at 9°C) should be injected at the same point during the respiratory cycle, at end-expiration. This may be difficult to achieve and in practice it is probably satisfactory to adopt random injection timing and derive an average value for cardiac output. Cardiac index is obtained by dividing the cardiac output by the body surface area: the normal range is 2.8 to 3.6 l/min.m².

Blood sampling from the pulmonary artery allows the determination of venous oxygen saturation (Svo&sub2;), venous oxygen tension (Pvo&sub2;), and venous oxygen content (Cvo&sub2;). This is obtained through the distal port of the catheter when it is in position in the pulmonary outflow tract. It is important that the specimen is aspirated slowly (3 ml/min) to avoid obtaining an arterialized specimen. The laboratory determination of Svo&sub2; is most accurately performed using an oximeter and should not be derived from the Pvo&sub2;. Pulmonary artery catheters incorporating direct continuous oximetry provide a unique facility to monitor Svo&sub2;.

Haemodynamic parameters can be derived using various formulae and a hand-held calculator or microcomputer, or can be calculated directly by newer generations of cardiac output computers or physiological monitors. The variables needed to calculate derived values are listed in Table 12 51. These derived haemodynamic parameters can be classified in two major categories, pump performance, and oxygen transport and utilization, and are shown in Table 13 52.

Cardiac index (cardiac output divided by body surface area) and stroke index (cardiac index divided by heart rate) relate cardiac output to the patient's body surface area. Systemic vascular resistance and pulmonary vascular resistance represent the peripheral component of afterload (that is, impedance). Their derived calculation is based on a rearrangement of Poiseuille's law (the hydraulic resistance equation): Equation 5

where R = resistance, P&subi; = pressure at inflow, P&subo; = pressure at outflow, Q = blood flow.

where MAP = mean (systemic) arterial pressure, CVP = central venous pressure, SVR = systemic vascular resistance, CO = cardiac output, PA = mean pulmonary arterial pressure, PAWP = pulmonary artery wedge pressure, and PVR = pulmonary vascular resistance.

Systemic vascular resistance is increased in low flow states, such as cardiogenic and hypovolaemic shock, secondary to endogenous or exogenous vasoconstrictors, and in systemic hypertension. It is decreased in states associated with high cardiac output, including trauma, sepsis, burns, liver disease, and anaemia, and in Addison's disease.

Pulmonary vascular resistance tends to be elevated in heart failure, pulmonary embolus, chronic obstructive pulmonary disease, adult respiratory distress syndrome, and mitral valve disease and decreased in vasodilated states and in hypovolaemia.

Left and right ventricular stroke work indices are derived parameters reflecting cardiac contractility. They are measures of the external work of the ventricle during each contraction and are represented as: Equation 7

where MAP = mean (systemic) arterial pressure, PA = mean pulmonary arterial pressure, and SI = stroke index (CI/HR).

The left ventricular stroke work index is elevated in some types of hypertension, aortic stenosis, and stress states (trauma, burns, and sepsis), and decreased in hypovolaemic, cardiogenic, and late septic shock. The right ventricular stroke work index is usually elevated in patients with pulmonary hypertension and valvular heart disease and decreased in hypovolaemic and cardiogenic shock. Identical stroke work indices can be obtained by doubling the stroke index and halving the pressure (volume work) or by halving the stroke index and doubling the pressure (pressure work). However, myocardial oxygen consumption is considerably greater when the heart is performing pressure work than when it is performing volume work. The extent of myocardial oxygen demand can be approximated using the rate–pressure product (heart rate × systolic blood pressure). Values above 12 000 are indicative of significantly increased myocardial work and increased myocardial oxygen demands.

Oxygen delivery is the amount of oxygen leaving the heart to be delivered to the tissues in ml/min (normal range 640–1200 ml/min) or, expressed as an index based on body surface area, the oxygen delivery index (normal range 500–720 ml/min.m²) Oxygen delivery indicates the integrity of the interactions between the cardiac pump, the oxygenating function of the lungs, and the carrying capacity of red blood cells. It does not provide an index of what the tissues do with the oxygen once it is delivered (oxygen uptake or extraction). Oxygen delivery is calculated from the product of cardiac output and the oxygen content of the blood (Cao&sub2; ml/dl of blood). Equation 8

Oxygen consumption is the amount of oxygen (in ml) consumed by the body's tissues per minute. Normal values range from 190 to 250 ml/min and the oxygen consumption index (corrected for body surface area) ranges from 100 to 160 ml/min.m². These variables are calculated as: Equation 9

In normal subjects, resting oxygen consumption is broadly unchanged over a wide range of values of oxygen, the oxygen extraction ratio varying to maintain a stable consumption. The normal physiological response to a fall in oxygen delivery is to increase oxygen extraction. Oxygen uptake, derived from analysis of inspired and expired respiratory gases, during steady state conditions will produce values equivalent to oxygen consumption.

The arteriovenous oxygen content difference is calculated as the difference between arterial and mixed venous oxygen content (Cao&sub2; − Cvo&sub2;). It is increased in conditions of increased oxygen extraction (decreased cardiac output, anaemia, and increased oxygen consumption) and may be decreased in high cardiac output states, in states associated with significant atrioventricular shunting, and with conditions in which impaired oxygen utilization occurs (sepsis). The oxygen extraction ratio is calculated as the arteriovenous oxygen content difference divided by the arterial oxygen content (Cao&sub2; − Cvo&sub2;) and reflects the fraction of delivered oxygen that is consumed: the normal range is 22 to 30 per cent. It varies in a similar way to the arteriovenous oxygen content difference.

A characteristic feature of cardiogenic shock is arterial hypoxaemia which, in association with the reduced cardiac output, causes profound falls in oxygen delivery and a subsequent rise in blood lactate. The administration of oxygen may improve haemodynamic parameters and produce a fall in lactate concentrations. The reduced oxygen delivery and hyperlactataemia are associated with an increase in oxygen extraction ratio and a marked reduction in venous oxygen saturation. The profound fall in venous oxygen saturation is of particular importance if the overall mixed venous saturation is less than 50 per cent, indicating that some tissues are significantly hypoxaemic. This results in anaerobic metabolism and increased lactic acid production. The treatment of cardiogenic circulatory failure should therefore be aimed at increasing cardiac output and at increasing venous oxygen saturation. The outcome of cardiogenic shock following acute myocardial infarction is considerably better in those patients whose cardiac index is greater than 2.2 l/min.m². Attempts should therefore be made to achieve cardiac indices greater than this using a combination of preload optimization, inotropes, and vasodilators, and then to maximize oxygen on-loading by supplemental oxygen and if necessary intubation and mechanical ventilation.

The alveolar-arterial oxygen gradient (A-aDO&sub2;) is a relatively sensitive but non-specific index of cardiopulmonary function. Gradients are normal when hypoxaemia is secondary to high altitude or alveolar hypoventilation (<2.6–3.3 kPa or 20–25 mmHg). In the presence of a normal cardiac output, the gradient provides a rough index of venous admixture and has the added advantage that a mixed venous blood sample is not required for its determination. However, it does require the Fio&sub2; to be accurately known. Determination of the gradient may offer predictive information—very high gradients are associated with severe cardiopulmonary disease—as well as offering a means to monitor therapy. It is calculated as: Equation 10

where PAo&sub2; = partial pressure of oxygen in alveolar air.

The shunt fraction (Qs/ Qt) measures the fraction of total blood flow that is not oxygenated during its passage through the lungs, and is calculated when the Fio&sub2; = 100 per cent. When it is calculated at an Fio&sub2; of below 100 per cent, it is more correctly referred to as the venous admixture (Qva/ Qt). Pulmonary conditions which cause shunting, such as pneumonia, atelectasis, and secretions, have primary effects on the shunt fraction. In patients who have diseased lungs, changes in shunt may simply reflect changes in pulmonary blood flow rather than changes in the intrinsic disease process. The effect of blood flow on shunt depends to some degree whether the lungs are normal, diffusely diseased, or have lobar or regional abnormalities. Venous admixture or shunt varies directly with cardiac output in patients with normal or diffusely abnormal lung (the higher the cardiac output, the greater the shunt) and inversely with cardiac output in patients with unilateral lung abnormalities. The resultant effect of cardiac output and shunt on the Pao&sub2; is complex and depends on whether the alteration in pulmonary shunt predominates over the change in mixed venous blood oxygen content.

The shunt equation is a mathematical derivation, partly based on the Fick equation. The derivation of the shunt equation involves making certain physiological assumptions which are in part theoretical. Since oxygen consumption represents the product of blood flow cardiac output times the atroventricular oxygen content difference (Cao&sub2; − Cvo&sub2;), the Fick equation, can be expressed as: Equation 11

The shunt equation is expressed as the ratio of oxygen content differences between pulmonary capillary blood (Cco&sub2;), an assumed quantity based on the knowledge of the partial pressure of oxygen in the alveolus PAo&sub2; and the oxygen content of arterial and mixed venous blood respectively. It is represented as: Equation 12

1.Obtain mixed venous blood through the distal line of the pulmonary artery catheter together with a direct pulmonary venous saturation if a fibreoptic pulmonary artery catheter has been used.

2.Measure arterial blood gases.

3.Calculate Cao&sub2; = (haemoglobin × 1.34 × Sao&sub2;) + (Pao&sub2; × 0.022)

4.Calculate Cvo&sub2; = (haemoglobin × 1.34 × Svo&sub2;) + (Pvo&sub2; × 0.022)

5.Calculate PAo&sub2; = (PB− 47)Fio&sub2;− (PaCo&sub2; × 1.25)

6.Calculate Cco&sub2; using PAo&sub2; from step 5, i.e. Cco&sub2; = (haemoglobin × 1.34 × Sco&sub2;) + (PAo&sub2; × 0.022) (assume Sco&sub2; = 100 per cent, a reasonable assumption providing the patient is on supplemental oxygen).

The normal shunt fraction is less than 10 per cent. Shunts below 10 per cent are rarely seen in patients receiving positive pressure ventilation. Calculated true shunts greater than 30 per cent are considered incompatible with prolonged spontaneous ventilation. Below 20 per cent the weaning process should be considered if the cardiac status is good.

Lactic acidosis is a pathological state characterized by persistent elevation of the serum lactate concentration together with significant acidaemia. Lactic acidosis should always be suspected in a patient with metabolic acidosis and an increased anion gap which cannot be explained by uraemia or ketonaemia. The onset of clinical manifestations may resemble diabetic ketoacidosis, with sudden malaise, weakness, anorexia, nausea, and vomiting. An early sign of lactic acidosis is hyperpnoea or abdominal pain. In contrast to diabetic ketoacidosis, there is no polyuria, polydipsia, or acetone odour, and the fluid deficit is usually less marked.

Lactic acidosis may occur during anaerobic conditions when oxidative metabolism via the Krebs' cycle or gluconeogenesis is prevented. It may be associated with impaired end-organ function, such as liver or kidney disease, which greatly decreases the metabolic capacity for lactate. Lactate is metabolized either via oxidative metabolism (Krebs' cycle) to CO&sub2; and H&sub2;O, or by gluconeogenesis to glucose. Both of these pathways depend on intact aerobic metabolism and need intact mitochondrial function, a favourable redox state, and adequate ATP. Gluconeogenesis from lactate occurs in the liver and kidneys and provide a continuous supply of glucose that would be otherwise wasted to tissues.

Increased lactate levels can exist without acidosis as is seen when lactate production exceeds metabolic capacity, even with intact oxidation metabolism, and good end-organ function. When this occurs (for example in hyperventilation and stress), pyruvate is converted to lactate. However, the elevation in lactate is generally modest (5 mmol/l) and acidosis, as noted above, is usually absent.

Type A lactic acidosis is associated with poor tissue perfusion and hypoxaemia and is the most common type. The initial hydrolysis of a relatively large amount of ATP would initially release more H⫀ than lactate.

Type B lactic acidosis not associated with a decreased oxygen supply and lactic acidosis is due to increased glycolysis or decreased gluconeogenesis. Hydrogen ion and lactate production tend to be equimolar. Type B lactic acidosis has been subdivided into three subtypes: type B&sub1; is associated with disorders such as diabetes mellitus, renal and hepatic disease, infection, and leukaemia; type B&sub2; is due to drugs, chemicals, and toxins such as phenformin, ethanol, and methanol; type B&sub3; covers congenital forms of lactic acidosis such as Von Gierke's disease.

Normal lactate levels are 0.5 to 1.6 mmol/l for arterial blood and 0.5 to 2 mmol/l for venous blood. It is essential that a tourniquet is not applied during venesection. Most patients with lactic acidosis have an anion gap that averages 22 to 27 mmol/l. The increase in the anion gap is usually greater than the decrease in HCO&sub3;&supminus;, in contrast to diabetic ketoacidosis, in which the increase in the anion gap is identical to the decrease in HCO&sub3;&supminus;.

Lactic acidosis is usually associated with tissue hypoxia, being common when cardiac output is greatly impaired but rare in patients with uncomplicated anaemia or hypoxaemia. As cardiac output decreases to 30 per cent of normal the major compensatory mechanism of increased oxygen extraction is insufficient to prevent tissue hypoxaemia. In the presence of arterial hypoxaemia and even severe anaemia, in tripling of cardiac output and a tripling of oxygen extraction results in a ninefold increase in oxygen delivery and ensures adequate oxygen delivery. Chronic lactic acidosis may develop in patients with severe congestive heart failure, and tissue hypoxia may exist in the presence of high cardiac output if blood distribution is disturbed, as occurs in the sepsis syndrome. The resolution of such a lactic acidosis is then considered a marker of efficacy of therapy provided liver function is unimpaired.

Lactic acidosis may accompany grand mal seizures and is generally self-limiting. Specific treatment of the acidosis is unnecessary, although resolution of lactic acidosis may be slower in patients with pre-existing liver disease.

Lactic acidosis used to be observed in patients with diabetes mellitus following phenformin administration; it is now rare since this side-effect was recognized. Lactic acidosis occasionally develops in patients with diabetic ketoacidosis and extreme volume depletion. It may also be evident in liver disease: basal lactate metabolism is generally normal in cirrhotics but the reserve is much decreased. Rising lactate levels in acute fulminant hepatitis are associated with a poor prognosis.

Lactic acidosis in association with hypoglycaemia is generally confined to infants and children, but has been noted occasionally in adults with either hepatic or renal disease.

Lactic acid levels are occasionally increased in patients with acute leukaemia, lymphomas, and intra-abdominal neoplasms. It has been attributed to the over-production of lactate by the tumour and appears to be related to the tumour burden.

Twenty per cent of asthmatics admitted to hospital may exhibit excess lactate production from the respiratory muscles, with some contribution from lactate under-utilization due to hypoperfusion of skeletal muscle and liver. The presence of lactic acidosis correlates with a peak expiratory flow rate of 60 l/min or less and might suggest that respiratory fatigue is imminent and that the patient may require ventilatory assistance.

Several drugs or toxins including, phenformin, salicylates, ethylene glycol, and methanol may be associated with lactic acidosis.

Therapy is directed at correcting or alleviating the underlying cause: this might include the administration of blood, fluids, and drugs to correct circulatory failure by optimizing myocardial performance. The underlying principle should be to maintain adequate levels of oxygen delivery. Mortality is high (>75 per cent) in patients with persistent lactic acidosis despite appropriate measures.

No specific form of current therapy has been shown to reduce the mortality rate associated with Type B lactic acidosis. Administration of sodium bicarbonate has been recommended to maintain the arterial pH above 7.2: below this there is myocardial depression and reduced cardiac output, while at a pH below 7.0, utilization of lactate by the liver is impaired. The dose of bicarbonate required can be estimated by multiplying the desired increase in HCO&sub3;&supminus;, in mmol, by 50 per cent of the patient's body weight in kg. However, bicarbonate stimulates glycolysis whilst depressing other oxidative reactions and therefore enhances lactate production. This increase in lactate production may contribute to the mortality associated with lactic acidosis. In diabetic ketoacidosis, bicarbonate delays the fall in blood lactate and total ketone bodies, even though it improves the pH. The relative risks and benefits of correcting a metabolic acidosis with bicarbonate are more thoroughly considered below.

Haemodialysis and peritoneal dialysis do not correct the cause of lactic acidosis but do restore the buffer pool. Dialysis and haemofiltration may supplement bicarbonate therapy by making space for additional fluid volume to be administered. Haemodialysis and haemofiltration fluids generally use lactate or acetate as the buffer. The buffering effect depends upon conversion to bicarbonate which may be impaired in patients with severe lactic acidosis or liver disease. In such circumstances a bicarbonate buffer may be preferable, with the above limitations being acknowledged.

Severe metabolic acidosis due to diabetic ketoacidosis, sepsis syndrome or renal failure is a common clinical problem in the critical care unit. Arguments have been voiced both for and against the use of specific alkalinizing agents to correct the acidosis rapidly in an attempt to avoid the complications of the acidotic state. Severe acidosis has several serious and life threatening effects, including circulatory failure due to reduce myocardial contractility, increased systemic and pulmonary vascular resistance, and enhanced arrhythmogenesis. In addition, end-organ receptor sensitivity to inotropes and pressors may be diminished, reducing the efficacy of these agents. Unfortunately, controlled studies of the effects of correction of metabolic acidosis with bicarbonate have failed to demonstrate improved haemodynamics. Additionally, and depending upon the alkalinizing agent selected, certain risks are associated with alkali therapy (Table 14) 53.

The convenience of arterial blood gas measurement, reflecting extracellular pH, has unfortunately diverted attention away from the need to correct intracellular acidosis. In addition, when tissue perfusion is poor, as occurs during cardiopulmonary resuscitation, arterial alkalaemia can coexist with venous and intracellular acidosis.

Several bicarbonate solutions are available, some of which include salts of weak acids such as citrate (Shohl's solution) or lactate (lactated Ringer's solution) and require the metabolism of these precursors to bicarbonate (Table 15) 54.

Hypertonic solutions are theoretically of advantage when hyponatraemia is present or in patients with circulatory overload. Isotonic solutions may be used when there is a risk of producing a hyperosmolar state or when volume expansion is desired. It is not unusual for patients with severe acidosis to require more than 200 mmol of bicarbonate per hour: such resistance to bicarbonate therapy usually denotes ongoing acid production, as might occur in a lactic acidosis secondary to sepsis. When bicarbonate neutralizes hydrogen ion CO&sub2; and H&sub2;O are produced according to the formula Equation 13

In the presence of an adequate circulation and alveolar ventilation the excess CO&sub2; is quickly eliminated by the lungs and pH restored to normal. In patients with circulatory collapse or ventilatory failure, CO&sub2; accumulates in the blood and, although the buffering capacity by bicarbonate is enhanced the effect upon pH is less than expected. Cell membranes are readily permeable to CO&sub2; (unlike bicarbonate and hydrogen ions), and intracellular pH may paradoxically fall following the administration of bicarbonate. This paradoxical response is of particular importance with regard to cerebral and cardiac function, resulting in raised intracranial pressure and refractory heart failure, respectively.

Hyperosmolality and hypernatraemia may be serious side-effects of sodium bicarbonate therapy, with each milliequivalent of bicarbonate providing twice the osmolar load. Severe and prolonged hypernatraemia can be associated with serious neurological sequelae including death.

Salt solutions of weak acids, such as acetate and lactate, can be used to improve base deficit indirectly. These act as bicarbonate precursors and are effective because of the subsequent generation of bicarbonate. The onset of effect is clearly slower than the equivalent doses of bicarbonate. Solutions which depend on hepatic metabolism to bicarbonate for their efficiency (e.g. lactated Ringer's, Shohl's solution) should be used with caution in patients with severe liver disease. Acetate is also contraindicated in diabetic ketoacidosis, when acetyl-CoA is already present in excess.

Tris-hydroxymethylaminomethane is an aminoalcohol which has an osmolality similar to that of plasma. A 0.3 M solution is a more powerful buffer than bicarbonate and produces a lower osmolar and sodium load than bicarbonate in equivalent doses. THAM should be infused slowly at rates not exceeding 2 mmol/min, to avoid an excessively rapid fall in arterial Pco&sub2;. After the infusion of 40 to 50 mmol, arterial blood gases can be repeated to assess benefit and determine whether further administration is required.

The buffering activity of THAM differs from bicarbonate in several important respects. By buffering carbonic acid, bicarbonate is generated and CO&sub2; is removed from plasma. By reducing extracellular and intracellular CO&sub2;, intracellular pH rises, unlike the situation following bicarbonate administration, which may exaggerate intracellular acidosis. The non-ionized fraction of THAM also diffuses directly into the intracellular space and acts as a buffer within the cell. THAM appears to have a positive inotropic and antiarrhythmic effect by correcting myocardial acidosis. Hypoventilation may occur following its administration due to the reduced CO&sub2; and resetting of chemoreceptor responsiveness, in which case mechanical ventilation may be required. Other, adverse effects of THAM are shown in Table 16 55.

Experimental evidence suggests that intraneuronal acidosis following head injury can be harmful and that THAM can correct intracerebral acidosis, reduce oedema, and improve the energy state of brain tissue. Preliminary results of a clinical trial of this therapy in severely head injured and comatose patients showed slightly improved survival.

Sodium carbonate acts as a hydrogen ion acceptor and a bicarbonate precursor. Carbonate preferentially buffers hydrogen ions, producing bicarbonate as follows: Equation 14

As with THAM sodium carbonate produces a fall in extracellular and intracellular CO&sub2;, and therefore reduces intracellular pH. However, it exerts no direct intracellular buffering due to its highly ionized state.

A combination of sodium carbonate and sodium bicarbonate (Carbicarb® ), has the attraction of bicarbonate (rapid activity without the need for metabolism to an active form) and the ability of carbonate to act as a CO&sub2; acceptor. Generally, a lower dose of Carbicarb is required compared to bicarbonate. In hypoxic lactic acidosis induced in animal models, Carbicarb proved superior to bicarbonate in correcting pH, reducing lactate levels, and protecting against hypotension.

Dichloroacetate has been shown to improve acidosis and support the circulation in some cases where bicarbonate therapy has failed. Dichloroacetate stimulates phosphodehydrogenase activity, increasing pyruvate oxidation, which in turn generates bicarbonate and reduces blood lactate levels. By this mechanism it is also able to reduce brain lactate more rapidly than is the case without therapy. Although dichloroacetate decreases the morbidity and mortality of experimentally induced lactic acidosis in dogs, it has yet to be shown to improve survival rates significantly in patients. There appear to be no major short-term complications from dichloroacetate therapy but chronic use carries a risk of drowsiness, paralysis, and polyneuropathy.

Braunwald E. On the difference between the heart's output and its contractile state. Circulation, 1971; 43: 171–74.

Berkowitz C, et al. Comparative responses of dobutamine and nitroprusside in patients with chronic low output cardiac failure. Circulation, 1977; 56: 918–24.

Callahan M, Barton C. Prediction of outcome of cardiopulmonary resuscitation from end-tidal carbon dioxide concentration. Crit Care Med, 1990; 18: 358–62.

Chatterjee K. Vasodilator therapy for heart failure. In: Cohn JN, ed. Drug treatment of heart failure. New York: York, 1983; 151–78.

Gaasch WH, Apstein CS, Levine HJ. Diastolic properties of the left ventricle. In: Levine HJ, Gaasch WH, eds. The ventricle: basic and clinical aspects. Boston: Martinus Nijhoff, 1985: 143–70.

Goldberg LI. Cardiovascular and renal actions of dopamine: potential clinical applications. Pharmacol Rev, 1972; 24: 1–29.

Krischer JK, Fine EG, Weifeldt ML, Guerci AD. Comparison of prehospital conventional and simultaneous compression–ventilation cardiopulmonary resuscitation. Crit Care Med, 1989; 17: 1263–69.

Royal College of Physicians. Resuscitation from cardiopulmonary arrest. Training and organisation. J R Coll Phys, 1987; 21: 1–8.

Wilson JR, Reichek N, Dunkman WB, Goldberg S. Effect of diuresis on the performance of the failing left ventricle in man. Am J Med, 1981; 70: 234–9.

Oxygen uptake, sepsis syndrome and multiple organ system failure

Alverdy JC, Aoys E, Moss GS. Total parenteral nutrition promotes bacterial translocation from the gut. Surgery, 1988; 104: 185–90.

Duff JH, et al. Defective oxygen consumption in septic shock. Surg Gynecol Obstet, 1969; 128: 1051–60.

Edwards JD, et al. Use of survivors' cardiorespiratory values as therapeutic goals in septic shock. Crit Care Med, 1989; 17: 1098–103.

Ledingham IMcA, Alcock SR, Eastaway AT, McDonald JC, McKay IC, Ramsay G. Triple regime of selective decontamination of the digestive tract, systemic cefotaxime and microbiological surveillance for prevention of acquired infection in intensive care. Lancet, 1988; i: 785–90.

Matushak GM, Rinaldo JE. Organ interactions in the adult respiratory distress syndrome during sepsis. Chest, 1988; 94: 400–6.

McArdle AH, Palmerson C, Brown RA, Brown HC, Williams HB. Early enteral feeding of patients with major burns: prevention of catabolism. Ann Plastic Surg, 1984; 13: 396–401.

Parker MM, et al. Profound but reversible myocardial depression in patients with septic shock. Ann Intern Med, 1984; 100: 483–90.

Ramsay G. Endotoxaemia in multiple organ failure: a secondary role for SDD. In: van Saene HKF, Stoutenbeek CP, Lawin P, Ledingham IMcA, eds. Infection control by selective decontamination. Berlin: Springer Verlag, 1989: 135–42.

Ravin HA, Rowley D, Jenkins C, Fine J. On the absorption of bacterial endotoxin from the gastrointestinal tract of the normal and shocked animal. J Exp Med, 1960; 112: 783–90.

Rush BF, et al. Endotoxaemia and bacteraemia during haemorrhagic shock. Ann Surg 1988; 207: 549–54.

Shibutani K, Komatsu T, Kubal K. Critical level of oxygen delivery in anaesthetized man. Crit Care Med, 1983; 11: 640–3.

Shoemaker WC, Appel PL, Kram HB. Prospective trail of supranormal values of survivors as therapeutic goals in high risk surgical patients. Chest, 1988; 94: 1176–218.

Shoemaker WC, Appel PL, Kram HB, Waxman K, Tai-Shion L. Prospective trial of supranormal values of survivors as therapeutic goals in high-risk surgical patients. Chest, 1988; 94: 1176–86.

Stoutenbeek CP, van Saene HKF, Miranda DR, Zandstra DF. The effect of selective decontamination of the digestive tract on colonisation and infection rate in multiple trauma patients. Intensive Care Med, 1984; 10: 185–92.

Wilmore DW, et al. The gut: a central organ after surgical stress. Surgery, 1988; 104: 917–23.

Wellman W, Fink TC, Benner F, Schmidt FW. Endotoxaemia in active Crohn's disease. Treatment with whole gut irrigation and 5-aminosalicylic acid. Gut, 1986; 27: 814–20.

Zieglar TR, et al. Increased intestinal permeability associated with infection in burn patients. Arch Surg, 1988; 123: 1313–19.

Baele PL, McMichan JC, Marsh HM, Sill JC, Southorn PA. Continuous monitoring of mixed venous oxygen saturation in critically ill patients. Anesth Analg, 1982; 61: 513–17.

Boyd KD, Thomas SJ, Gold J, Boyd AD. A prospective study of complications of pulmonary artery catheterizations in 500 consecutive patients. Chest, 1983; 84: 245–9.

Forrester JS, Diamond GA, Swan HJC. Correlative classification of clinical and hemodynamic function after acute myocardial function. Am J Cardiol, 1977; 39: 137–45.

Groeneveld ABJ, Thijs LG. Pulmonary artery catheterization in septic shock. Clin Intensive Care, 1990; 1: 111–15.

Guyton AC, Lindsey AW. Effect of elevated left atrial pressure and decreased plasma protein concentration on the development of pulmonary edema. Circ Res, 1959; 7: 649–57.

Lategola M, Rahn H. A self guiding catheter for cardiac and pulmonary arterial catheterization and occlusion. Proc Soc Exp Biol Med, 1953; 84: 667–8.

Pinilla JC, Ross DF, Martin T, Crumb H. Study of the incidence of intravascular catheter infections and associated septicaemia in critically ill patients. Crit Care Med, 1983; 11: 21–5.

Robin ED. The cult of the Swan-Ganz catheter: Overuse and abuse of pulmonary flow catheters. Ann Intern Med, 1985; 103: 445–9.

Shah KB, Rao TK, Langhlin S, El-Etr A. A review of pulmonary artery catheterization in 6,245 patients. Anesthesiology, 1984; 61: 271–5.

Stevenson LW, Perloff JK. The limited reliability of physical signs for estimating hemodynamics in chronic heart failure. JAMA, 1989; 261: 884–8.

Swan HJC, Ganz W, Forrester J, Marcus H, Diamond G, Chonette D. Catheterization of the heart in man with use of a flow-directed balloon tipped catheter. N Engl J Med, 1970; 283: 447–51.

Vincent J-L, Thirion M, Brimioulle S, Lejeune P, Kahn RJ. Thermodilution measurement of right ventricular ejection fraction with a modified pulmonary artery catheter. Intensive Care Med, 1986; 12: 33–8.

Bersin RM, Arieff AI. Improved hemodynamic function during hypoxia with Carbicarb, a new agent for the management of acidosis. Circulation, 1988; 77: 227–33.

Effron MB, Guarnieri T, Frederkisen JW, Greene HL, Weisfeldt ML. Effects of tris (hydroxymethyl) aminomethane on ischemic myocardium. Am J Physiol, 1978; 235: H167–74.

Jaffe AS. New and old paradoxes. Acidosis and cardiopulmonary resuscitation. Circulation, 1989; 80: 1079–83.

Kruse JA, Haupt, MT, Puri VK, Carlson, RW. Lactate levels as predictors of the relationship between oxygen delivery and consumption in ARDS. Chest, 1990; 98: 959–62.

Rosner MJ, Elias KG, Coley I. Prospective, randomized trial of THAM therapy in severe brain injury: preliminary results. In Hoff JT, Betz AL, eds. Intracranial Pressure VII. Berlin: Springer, 1989: 611–15.

Shapiro JI. Functional and metabolic responses of isolated hearts to acidosis: effects of sodium bicarbonate and Carbicarb. Am J Physiol, 1990; 258: H1835–9.

Stacpoole PW. Lactic acidosis: the case against bicarbonate therapy. Ann Intern Med, 1986; 105: 276–9.

Stacpoole PW, Lorenz, AC, Thomas RG, Harman EM. Dichloroacetate in the treatment of lactic acidosis. Ann Intern Med, 1988; 108: 58–63.

von Gazmuri RJPM, Weil MH, Rackow, EC. Cardiac effects of carbon dioxide-consuming and carbon dioxide-generating buffers during cardiopulmonary resuscitation. J Am Coll Cardiol, 1990; 15: 482–90.

Weil MH, Ruiz CE, Michaels S, Rackow EC. Acid base determinants of survival after cardiopulmonary resuscitation. Crit Care Med, 1985; 13: 888–92.