Category Archives: Intensive care medicine

Microcirculatory changes

Since shock is a syndrome caused by inadequate tissue perfusion, the final common pathway for the pathophysiological changes is the microcirculation. In the early stages of septic shock there is vasodilatation, maldistribution of flow, arteriovenous shunting and increased capillary permeability with interstitial oedema. Although these microvascular abnormalities may largely account for the reduced oxygen extraction often seen in septic shock there may also be a primary defect of cellular oxygen utilization. Initially, before hypovolaemia supervenes, or when therapeutic replacement of circulating volume has been adequate, cardiac output is usually high and peripheral resistance low. Vasodilatation and increased capillary permeability also occur in anaphylactic shock.
In the initial stages of other forms of shock, and sometimes when hypovolaemia supervenes in sepsis and anaphylaxis, increased sympathetic activity causes constriction of both precapillary arterioles and, to a lesser extent, the postcapillary venules. This helps to maintain the systemic blood pressure. In addition, the hydrostatic pressure within the capillaries falls and fluid is mobilized from the extravascular space into the intravascular compartment. If shock persists, the accumulation of metabolites, such as lactic acid and carbon dioxide, combined with the release of vasoactive substances, causes relaxation of the precapillary sphincters, while the postcapillary venules, which are more sensitive to hypoxic damage, become relatively unresponsive to these substances and remain constricted. Blood is therefore sequestered within the dilated capillary bed and fluid is forced into the extravascular spaces, causing interstitial oedema, haemoconcentration, and an increase in viscosity.
This reduction in flow through the microcirculation, combined with the increase in viscosity, makes the blood highly coagulable. There is also systemic activation of the clotting cascade and platelet aggregation with clot formation  occurring within the capillary bed. Plasminogen is  converted to plasmin, which breaks down these clots, liberating fibrin/fibrinogen degradation products (FDPs). The cells that are supplied by capillaries blocked by this process of disseminated intravascular coagulation (DIe) (see p. 345) inevitably become hypoxic and eventually die. Tissue ischaemia is further exacerbated as capillaries  are compressed by interstitial oedema. In this way vital organs may suffer serious damage. Finally, because clotting factors and platelets are consumed in DIe, they are unavaila le for haemostasis elsewhere and a coagulation defect results-hence the alternative name for DIe of consumption coagulopathy’. This process occurs earlier and is more severe in septic shock. The capillary endothelium can be damaged by a number of factors (particularly in septic shock), including DIe, micro emboli, release of vasoactive compounds, complement, and activated leucocytes. Capillary permeability is thereby increased and fluid is lost into the extravascular space, causing further hypovolaemia, interstitial oedema and organ dysfunction.

Metabolic changes

Gluconeogenesis and triglyceride formation are stimulated by increased glucagon and catecholamine levels, whilst glucagon increases hepatic mobilization of glucose from glycogen. Catecholamines inhibit insulin release and reduce peripheral glucose uptake. Combined with elevated  circulating levels of other insulin antagonists such as cortisol and GH these changes ensure that the majority of shocked patients are hyperglycaemic. Occasionally hypoglycaemia is precipitated by depletion of hepatic glycogen stores and inhibition of gluconeogenesis. Muscle proteolysis is initiated to provide energy and hepatic protein synthesis is preferentially augmented to produce the ‘acute phase reactants’.
Once the supply of oxygen to the cells is insufficient for continuation of the tricarboxylic acid (TeA) cycle, production of energy in the form of ATP becomes dependent on anaerobic metabolism. Under these circumstances, glucose is metabolized in the normal way to pyruvate but is then converted to lactate instead of entering the Krebs cycle. The H+ ions released cause a metabolic acidosis. This pathway is relatively inefficient in terms of energy production. Eventually, because of the reduced availability of ATP, the sodium pump fails, cells  swell due to accumulation of salt and water, and potassium losses increase. In the final stages, release of lysosomal enzymes may contribute to cell death.

Multiple organ failure (MOF)

Impaired tissue perfusion, microcirculatory abnormalities, and defective oxygen utilization precipitated by dissemination of the inflammatory response with the systemic release of ‘mediators’ (see above) can damage vital organs. The most severely ill patients may develop MOF,  which is almost invariably associated with persistent or recurrent sepsis. Following severe shock, damage to the mucosa of the gastrointestinal tract may allow bacteria or endotoxin Within the gut lumen to gain access to the circulation, thereby perpetuating the generalized inflammatory response. Sequential failure of organs occurs progress ively over weeks, although the pattern of organ dysfunction is variable. In most cases the lung is the first organ to be affected with the development of the adult respiratory distress syndrome (ARDS) (see below) in association with cardiovascular instability and deteriorating renal function. Secondary pulmonary infection is common in ARDS, acting as a further stimulus to the inflammatory response. Later, liver and renal failure develop. Characteristically, these patients initially have a hyperdynamic circulation with vasodilatation and a high cardiac output. Eventually, however, cardiovascular collapse supervenes and is the usual terminal event.
Treatment is supportive and prevention of organ damage in those at risk is therefore crucial. Aggressive resuscitation is essential and activation of macrophages must be prevented or minimized by early excision of devitalized tissue and drainage of infection. Preservation of the integrity of the gut mucosal barrier is also necessary by aggressive haemodynamic support in order to maximize splanchnic perfusion. Early enteral feeding may also be beneficial. Early recognition of organ dysfunction and prompt intervention may reverse organ impairment and improve outcome.
The mortality of MOF is extremely high; factors affecting outcome include the number of organs that fail and the duration of organ failure.

Acute disturbances of haemodynamic function (shock)

Shock is difficult to define. The term is used to describe acute circulatory failure with inadequate or inappropriately distributed tissue perfusion resulting in generalized cellular hypoxia.

Causes

The causes are shown. Very often shock can result from a combination of these factors.

PATHOPHYSIOLOGY

Sympatho-adrenal response to shock

Hypotension stimulates the baroreceptors, and to a lesser extent the chemoreceptors, causing increased sympathetic nervous activity. Later this is augmented by the release of catecholamines from the adrenal medulla. The resulting vasoconstriction, together with increased myocardial contractility and heart rate, helps to restore blood pressure and cardiac output.
Reduction in perfusion of the renal cortex stimulates the juxtaglomerular apparatus to release renin. This converts angiotensinogen to angiotensin I, which is in turn converted in the lungs to the potent vasoconstrictor angiotensin II. Angiotensin II also stimulates secretion of aldosterone by the adrenal cortex, causing sodium and water retention. This helps to restore the circulating volume.

Causes of shock.

Causes of shock.

Neuroendocrine response to shock

RELEASE OF PITUITARY HORMONES: adrenocorticotrophic hormone (ACTH), growth hormone (GH), vasopressin (antidiuretic hormone, ADH) and f3- endorphin. (Endogenous opioid peptides such as f3- endorphin, dynorphin and the enkephalins may be partly responsible for some of the cardiovascular changes.)
RELEASE OF CORTISOL, which causes fluid retention and antagonizes insulin.
RELEASE OF GLUCAGON, which raises blood sugar. Release of mediators
The presence of severe infection (often with bacteraemia or endotoxaemia) or of large areas of devitalized tissue (e.g. following trauma or major surgery) can trigger a massive inflammatory response with systemic activation of leucocytes and release of a variety of potentially damaging ‘mediators’. Although clearly beneficial when targeted against local areas of infection or necrotic tissue, dissemination of this response can produce widespread tissue damage.

Microorganisms and their toxic products

In septic shock the inflammatory cascade is triggered by the presence of microorganisms, their toxic products (e.g. endotoxin) or both in the bloodstream. Endotoxin is a lipopolysaccharide derived from the cell wall of Gramnegative bacteria which is thought to be a particularly important trigger of septic shock.

Activation of complement cascade

One of the many functions of the complement system is to attract and activate leucocytes, which then marginate on to endothelium and release inflammatory mediators such as proteases and toxic oxygen radicals; these can produce local tissue damage. For example, the free radical  superoxide (02-) can participate in a number of chemical reactions, yielding hydrogen peroxide (H202) and hydroxyl radicals (OH-), which can damage cell membranes, interfere with the function of a number of enzyme systems and increase capillary permeability.

Cytokines

Macrophage and lymphocyte-derived cytokines such as the interleukins (ILs) and tumour necrosis factor (TNF) are involved in the pathogenesis of shock. TNF release initiates many of the responses to endotoxin and acts synergistically with IL-l, in part through induction of cyclooxygenase, platelet activating factor (PAF) and nitric oxide synthase.

The sympatho-adrenal response to shock.

The sympatho-adrenal
response to shock.

Platelet -activating factor

This vasoactive lipid is released from various cell populations, such as leucocytes and macrophages, in shock. Its effects, which are caused both directly and through the secondary release of other mediators, include hypotension, increased vascular permeability and platelet  aggregation.

Products of arachidonic acid metabolism

Arachidonic acid, derived from the increased breakdown of membrane phospholipid, is metabolized to form prostaglandins and leukotrienes, which are important inflammatory mediators. Prostaglandins currently thought to be of importance in shock include:
• Prostacyclin, which is a vasodilator and inhibits platelet aggregation
• Thomboxane A2, which causes pulmonary vasoconstriction and activates platelets
• Prostaglandin F2a, which may be responsible for the early phase of pulmonary hypertension commonly seen in experimental septic shock.
Leukotrienes have a variety of effects including reduction in cardiac output, vasoconstriction, increased vascular permeability and platelet activation.

Lysosomal enzymes

These are released in response to hypoxia, ischaemia, sepsis and acidosis. As well as being directly cytotoxic, they can cause myocardial depression and coronary vasoconstriction. Furthermore, lysosomal enzymes can convert inactive kininogens, which are usually combined with {X2-globulin, to vasoactive kinins such as bradykinin. These substances can cause vasodilatation and increased capillary permeability, as well as myocardial depression. They can also activate clotting mechanisms. Endothelium-derived vasoactive mediators Endothelial cells synthesize a number of mediators which contribute to the regulation of blood vessel tone and the fluidity of the blood; these include prostacyclin, endothelin- l and endothelium-derived relaxing factor (EDRF). The latter has now been identified as nitric oxide (NO) which is synthesized from L-arginine under the influence of NO synthases. Increased NO production is responsible for the sustained vasodilatation and hyporeactivity to adrenergic agonists which is seen in septic shock and may also be involved in severe haemorrhagicltraumatic shock. Endothelin-l is a potent vasoconstrictor, but its role in shock is not yet well understood.

Endothelial leucocyte adhesion molecule

This molecule is expressed on endothelial cells after exposure to inflammatory mediators, including TNF, and is involved in the adhesion of polymorphonuclear cells to the endothelium. This is considered to be one of the earliest steps in the cascade of events leading to tissue damage and adhesion molecules may therefore play an important role in the pathogenesis of organ failure.

Mixed venous P02 (P902)

This is the partial pressure of oxygen in pulmonary arterial blood that has been thoroughly mixed during its passage through the heart. If Pa02 remains constant, the PV<>2 will fall if more oxygen has to be extracted from each unit volume of blood arriving at the tissues. A fall in PV<>2 therefore indicates that either oxygen delivery has fallen or that tissue oxygen requirements have increased without a compensatory rise in cardiac output. If PV<>2 falls, the effect of a given degree of pulmonary shunting on arterial oxygenation will be exacerbated. Thus, worsening arterial hypoxaemia does not necessarily indicate a deterioration in pulmonary function but may instead reflect a fall in cardiac output and/or a rise in oxygen consumption.
The Pv02 is also influenced by the position of the oxyhaemoglobin dissociation curve, a factor not incorporated in the concept of oxygen flux. Thus, if the arteriovenous oxygen content difference remains constant, a shift of the curve to the right, which occurs with acidosis, hypercarbia, pyrexia and a rise in red cell 2,3- diphosphoglycerate (2,3-DPG) levels, may cause the Pv02 to rise. If the Pv02 remains unchanged, more oxygen will be unloaded at tissue level. A shift of the curve to the left, on the other hand, will cause a fall in the Pv02′ It might be argued, then, that under certain circumstances an acidosis may be beneficial in terms of tissue oxygenation, provided that it is not severe enough to interfere with cardiac function. It is probable though, that shifts of the dissociation curve are of little clinical significance.

The carbon dioxide dissociation curve.

The carbon dioxide dissociation curve.

Oxyhaemogiobin dissociation curve

The saturation of haemoglobin with oxygen is determined by the partial pressure of oxygen (P02) in the blood, the relationship between the two being described by the oxyhaemoglobin dissociation curve. The sigmoid shape of this curve is important clinically for a number of reasons:
• Falls in Pa02 may be tolerated provided that the percentage saturation remains above 90%.
• Increasing the Pa02 to above normal has only a minimal effect on oxygen content unless hyperbaric oxygen is administered (when the amount of oxygen in solution in plasma becomes significant).
• Once on the steep ‘slippery slope’ of the curve, a small decrease in Pa02 can cause large falls in oxygen content, while increasing Pa02 only slightly (e.g. by administering 28% oxygen to a patient with chronic bronchitis) can lead to useful increases in oxygen saturation.
The Pao2 is in turn influenced by the alveolar oxygen tension (PA02), the efficiency of pulmonary gas exchange, and the partial pressure of oxygen in mixed venous blood (PV<>2)·

The oxyhaemoglobin

The oxyhaemoglobin

Alveolar oxygen tension

The partial pressures of inspired gases. By the time the inspired gases reach the alveoli they are fully saturated with water vapour at body temperature (37°C), which has a partial pressure of 6.3 kPa (47 mmHg) and contains CO2 at a partial pressure of approximately 5.3 kPa (40 mmHg). The PA02 is thereby reduced to approximately l3.4 kPa (100 mmHg). The clinician can influence PA02 by administering oxygen or increasing the barometric pressure (i.e. administering hyperbaric oxygen). Because of the reciprocal relationship between the partial pressures of oxygen and carbon dioxide in the alveoli, a small increase in PA02 can be produced by lowering the PAC02 (e.g. using mechanical ventilation).

Pulmonary gas exchange

In normal subjects there is a small alveolar-arterial oxygen difference (PA-a02). This is due to:
• A small (0.133 kPa, 1 mmHg) pressure gradient across the alveolar membrane
• A small amount of blood (2% of total cardiac output) bypassing the lungs via the bronchial and thebesian veins
• A small ventilation/perfusion mismatch Pathologically there are three causes of a PA-a02 difference: DIFFUSION DEFECT. This is not an important cause of hypoxaemia even in conditions such as fibrosing alveolitis, in which the alveolar capillary membrane is considerably thickened. Certainly carbon dioxide is not affected, as it is much more soluble than oxygen.

The partial pressures of inspired

The partial pressures of inspired

RIGHT-TO-LEFT SHUNTS. In certain congenital cardiac lesions, e.g. Fallot’s tetralogy and when a segment of lung is completely unventilated, a large amount of blood bypasses the lungs and causes arterial hypoxaemia. This hypoxaemia cannot be corrected by administering oxygen to increase the PA02, because blood leaving normal alveoli is already fully saturated and further increases in P02 will not significantly affect its oxygen content. On the other hand, because of the shape of the carbon dioxide dissociation curve, the high Pco; of the shunted blood can be compensated for by overventilating patent alveoli, thus lowering the CO2 content of the effluent blood. Indeed, many patients with acute right-to-left shunts hyperventilate in response to the hypoxia or stimulation of mechanoreceptors in the lung, so that the Pac02 is normal or low.
VENTILATION/PERFUSION (VIQ) MISMATCH.This is discussed in more detail in Chapter 12. Diseases of the lung parenchyma result in a VIQ mismatch, producing an increase in alveolar dead space and hypoxaemia. The former can be compensated for by increasing overall ventilation. In contrast to the hypoxia resulting from a true right-to-Ieft shunt (see above), that due to areas of low VIQ can be partially corrected by administering oxygen and thereby increasing the PA02 even in poorly ventilated areas of lung.

Oxygen delivery

Oxygen delivery (oxygen flux) is defined as the total amount of oxygen delivered to the tissues per unit time. It is dependent on the volume of blood flowing through the microcirculation per minute (i.e. the total cardiac output – Q,) and the amount of oxygen contained in that blood (i.e. the arterial oxygen content- C.02). Oxygen is transported in combination with haemoglobin or dissolved in plasma. The amount combined with haemoglobin is determined by the oxygen capacity of the haemoglobin (usually taken as 1.34 ml O2 per gram of haemoglobin) and its percentage saturation with oxygen (So2)’ while the volume dissolved in plasma depends on the partial pressure of oxygen (P02). Except when hyperbaric oxygen is administered, the amount of dissolved oxygen in plasma is sufficiently small to be ignored for most practical purposes.
Clinically, however, the concept of oxygen flux provides little information about the relative flow to individual organs. Furthermore, some organs have high oxygen requirements relative to their blood flow and maybecome hypoxic even if the overall oxygen flux is apparently adequate.

CARDIAC OUTPUT

Cardiac output is the product of heart rate and stroke volume, and is affected by changes in either.

Heart rate

Increased heart rate

When heart rate increases, the duration of systole remains essentially unchanged, whereas diastole, and thus the time available for ventricular filling, becomes progressively shorter, and the stroke volume eventually falls. In the normal heart this occurs at rates greater than about 160 beats per minute, but in those with cardiac pathology, especially when this restricts ventricular filling (e.g. mitral stenosis), stroke volume may fall at much lower heart rates. Furthermore, tachycardias cause a marked increase in myocardial oxygen consumption and this may precipitate ischaemia in areas of the myocardium that have reduced coronary perfusion.
Decreased heart rate When the heart rate falls, a point is reached at which the increase in stroke volume is insufficient to compensate for the bradycardia and again cardiac output falls. Alterations in heart rate are often caused by disturbances of rhythm (e.g. artrial fibrillation, complete heart block or junctional arrhythmias), in which ventricular filling is not augmented by atrial contraction and stroke volume therefore falls.

Stroke volume

Three factors determine the stroke volume: pre-load, myocardial contractility and after-load.

Pre-load

This is defined as the tension of the myocardial fibres at the end of diastole, just before the onset of ventricular contraction, and is therefore related to the degree of stretch of the fibres. As the end-diastolic volume of the ventricle increases, tension in the myocardial
fibres is increased and stroke volume .rises.
Myocardial oxygen consumption (Vm02) increases only slightly with an increase in pre-load and this is therefore the most efficient way of improving cardiac output.

Myocardial contractility

This refers to the ability of the heart to perform work, independent of changes in pre-load and after-load. The state of myocardial contractility determines the response of the ventricles to changes in pre-load and after-load. Contractility is often reduced in intensive care patients, either as a result of pre-existing myocardial damage, e.g. ischaemic heart disease, or the acute disease process itself. Changes in myocardial contractility alter the slope and position of the Starling curve; the resulting worsening ventricular performance is manifested as a depressed, flattened curve.

The determinants of cardiac output.

The determinants of cardiac output.

The relationship between myocardial

The relationship between myocardial

Ventricular function (Starling curve).

Ventricular function (Starling curve).

The effect of changes in after-load

The effect of changes in after-load

After-load

This is defined as the myocardial wall tension developed during systolic ejection. In the case of the left ventricle the resistance imposed by the aortic valve, the peripheral vascular resistance and the elasticity of the major blood vessels are important determinants of after -load. Decreasing the after-load can increase the stroke volume achieved at a given pre-load, whilst also reducing the ventricular wall tension and the myocardial oxygen consumption. The reduction in wall tension may lead to an increase in coronary blood flow, thereby improving the myocardial oxygen supply-demand ratio. Excessive reductions in after-load will cause hypotension. An increase in after-load, on the other hand, can cause afall in stroke volume and is a potent cause of increased Vm02. Right ventricular after-load is normally negligible because the resistance of the pulmonary circulation is very low.

OXYGENATION OF THE BLOOD

Oxygen content (Ca02) is dependent on the amount of haemoglobin present per unit volume of blood, its oxygen capacity and its percentage saturation with oxygen. For this reason, maintenance of an ‘adequate’ haemoglobin concentration is essential in critically ill patients. Tissue oxygenation is, however, also dependent on blood flow. This is in turn determined not only by the cardiac output and its distribution, but also by the viscosity of the blood. The latter depends largely on the packed cell volume (PCv) and it is generally considered that the optimal balance between oxygen-carrying capacity and tissue flow is achieved at a PCV of approximately 30-35%.

Intensive care medicine

Introduction

Intensive care medicine (or ‘critical care medicine’) is concerned predominantly with the management of patients with acute life-threatening conditions (‘the critically ill’) in a specialized unit. It also encompasses the resuscitation and transport of those who become acutely ill, or are injured, either elsewhere in the hospital or in the community. Ai; well as emergency cases, intensive care units admit high-risk patients electively after major surgery.
An intensive care unit is fully equipped with monitoring and technical facilities, including an adjacent laboratory for the rapid determination of blood gases and simple biochemical data such as serum potassium and blood glucose. Patients can receive continuous expert nursing care and the constant attention of appropriately trained medical staff. These conditions and facilities are not available on a general ward. Teamwork and a multidisciplinary approach is central to the provision of intensive care and is most effective when directed and coordinated by a committed specialist. In the UK about 1% of the acute beds in the hospital are usually allocated to intensive care, but elsewhere in the developed world the proportion is often much higher.

Some common indications for admission to intensive care.

Some common indications for admission to intensive care.

In all critically ill patients, the immediate objective is to preserve life and prevent, reverse or minimize damage to vital organs such as the brain and the kidneys. This is achieved by supporting cardiovascular and respiratory function in order to maximize delivery of oxygen to the  tissues.
This chapter concentrates on cardiovascular and respiratory problems. Many patients have failure of other  organs such as the kidney and liver as well; treatment of these is dealt with in more detail in the appropriate chapters. Feeding the critically ill patient