Respiratory failure, including ards

Respiratory failure, including ards - The majority of patients admitted to ICU/HDU have respiratory problems either as the primary cause of admission or secondary to pathology elsewhere. Respiratory failure is classified on the basis of blood gas analysis as:

diaphragm, rib cage, pulmonary arteries, brain, and spinal cord in the body. Figure B shows the major conditions that cause respiratory failure.

Respiratory failure

• type 1: hypoxaemia (PaO2 < 8 kPa (< 60 mmHg) when breathing air) without hypercapnia caused

by a failure of gas exchange due to mismatching of pulmonary ventilation and perfusion

• type 2: hypoxaemia with hypercapnia (PaCO2 > 6.5 kPa (> 49 mmHg)) due to alveolar hypoventilation which occurs when the respiratory muscles cannot perform sufficient work to clear the carbon dioxide produced by the body.

Although this distinction is conceptually useful, it cannot be applied too rigidly in critically ill patients since they may change from type 1 to 2 as their illness progresses; hypercapnia may develop in pneumonia or pulmonary oedema as the patient tires and can no longer sustain the increased work of breathing. Pulmonary problems in critically ill patients can also be classified according to the functional residual capacity (FRC, or the lung volume at the end of expiration). Examples of low FRC include lung collapse, pneumonia and pulmonary oedema; examples of high FRC (i.e. over-distended lungs) include asthma, COPD and bronchiolitis.

This allows logical management directed at improving lung compliance and reducing the work of

breathing. The more common causes of acute respiratory failure presenting to ICU/HDU for respiratory support are shown in Box 8.6. The presentation, differential diagnosis and initial treatment of the primary respiratory conditions causing acute respiratory failure are covered

in Chapter 19. The assessment of respiratory failure in the critically ill patient should be guided by several important principles: The patient’s appearance (tachypnoea, 

• difficulty speaking in complete sentences, laboured breathing, exhaustion, agitation or increasing

obtundation) is more important than measurement of blood gases in deciding when it is appropriate

to provide mechanical respiratory support or intubation.

• Adequate supplemental oxygen to maintain SpO2 > 94% should be provided. If the inspired oxygen concentration required exceeds 60%, refer to the critical care team.

• Measurement of SpO2 and ABGs is essential in monitoring progress.

• Restless patients dependent on supplementary oxygen or with deteriorating conscious level are at risk. If they remove the mask or vomit, the resulting hypoxaemia or aspiration may be catastrophic.

• An attempt should be made to reduce the work of breathing, e.g. by treating bronchoconstriction or

using CPAP (see below)

Systemic inflammation

Systemic inflammation - During a severe inflammatory response, systemic release of cytokines and other mediators triggers widespread interaction between the coagulation pathways, platelets, endothelial cells and white blood cells, particularly the polymorphonuclear cells (PMNs). These ‘activated’ PMNs express adhesion factors (selectins), causing them initially to adhere to and roll along the endothelium, then to adhere firmly and migrate through the damaged and disrupted endothelium into the extravascular, interstitial space together with fluid and proteins, resulting in tissue oedema and inflammation.

Systemic Inflamation

Inflammation

A vicious circle of endothelial injury, intravascular coagulation, microvascular occlusion, tissue damage and further release of inflammatory mediators ensues. All organs may become involved. This manifests in the lungs as the acute respiratory distress syndrome (ARDS) and in the kidneys as acute tubular necrosis (ATN), while widespread disruption of the coagulation system results in the clinical picture of DIC.

The endothelium itself produces mediators that control blood vessel tone locally: endothelin 1, a potent vasoconstrictor, and prostacyclin and nitric oxide (NO, p. 82), which are systemic vasodilators. NO (which is also generated outside the endothelium) is implicated in both the myocardial depression and the profound vasodilatation of both arterioles and venules that causes the

relative hypovolaemia and systemic hypotension found in septic/systemic inflammatory response syndrome (SIRS) shock.

A major component of the tissue damage in septic/SIRS shock is the inability to take up and use oxygen at mitochondrial level, even if global oxygen delivery is supranormal. This effective bypassing of the tissues results in a reduced arteriovenous oxygen difference, a low oxygen extraction ratio, a raised plasma lactate and a paradoxically high mixed venous oxygen saturation (SvO

Adverse drug reactions

Adverse drug reactions - Adverse drug reactions (ADRs) and the effects of drug interactions are discussed on pages 31–35. They may result in symptoms, abnormal physical signs and altered laboratory test results (Box 7.11). ADRs are the cause of around 5% of all hospital admissions but account for up to 20% of admissions in those aged over 65 years. This is partly because older people receive many more prescribed drugs than younger people. Polypharmacy is defined as the use of four or more drugs but may not always be inappropriate, as many conditions such as hypertension and heart failure dictate the use of several drugs, and older people may have several coexisting medical problems. 

Adverse Drug Reactions (ADRs)

Adverse Drug Reactions Second Edition

However, the more drugs that are taken, the greater the risk of an ADR. This risk is compounded by age-related changes in pharmacodynamic and pharmacokinetic factors (pp. 28–29), and by impaired homeostatic mechanisms, such as baroreceptor responses, plasma volume and electrolyte control Older people are thus especially sensitive to drugs that can cause postural hypotension or volume depletion (see Box 7.11). Non-adherence to drug therapy also rises with the number of drugs prescribed.

The clinical presentations of ADRs are diverse, so for any presenting problem in old age the possibility that the patient’s medication is a contributory factor should always be considered. Failure to recognise this may lead to the use of a further drug to treat the problem, making matters worse, where the better course would be to stop or reduce the dose of the offending drug or to find an alternative.

Several factors contribute to polypharmacy (Box 7.12), and it has been shown that most ADRs are preventable. This is achieved by using as few drugs as possible, at the lowest dose possible in easy-to-take formulations, by ensuring that the patient understands the dosage regime, and by reviewing medication regularly. The patient or carer should be asked to bring all medication for review rather than the doctor relying on previous records. Those drugs that are no longer needed or that are contraindicated can then be discontinued.

Frailty

Frailty - Frailty is defined as the loss of an individual’s ability to withstand minor stresses because the reserves in function of several organ systems are so severely reduced that even a trivial illness or adverse drug reaction may result in organ failure and death. The same stresses would cause little upset in a fit person of the same age.

older people is a Frailty

It is important to understand the difference between ‘disability’ and ‘frailty’. Disability indicates established loss of function (e.g. mobility; see Box 7.15, p. 175), while frailty indicates increased vulnerability to loss of function. Disability may arise from a single pathological event (such as a stroke) in an otherwise healthy individual. After recovery, function is largely stable, and the patient may otherwise be in good health. When frailty and disability coexist, function deteriorates markedly even with minor illness, to the extent that the patient can no longer manage independently.

Unfortunately, the term ‘frail’ is often used rather vaguely, sometimes to justify a lack of adequate investigation and intervention in older people. However, it can be specifically identified by assessing function in a number of domains (Box 7.2). These are all commonly impaired by disease, illness and indeed age, but can often be improved by specific intervention. In clinical practice, ‘frailty’ per se is rarely measured formally, but a comprehensive assessment (see below) includes an evaluation of each domain.

Frail older people particularly benefit from a clinical approach that addresses both the precipitating acute illness and their underlying loss of reserves. It may be possible to prevent further loss of function through early intervention; for example, a frail woman with cardiac failure will benefit from specific cardiac investigation and drug treatment, but will benefit even further from an exercise programme to improve musculoskeletal function, balance and aerobic capacity, with nutritional support to restore lost weight. Establishing a patient’s level of frailty also helps inform decisions regarding further investigation and management, and the need for rehabilitation.

Oxygen transport

Oxygen transport - The major function of the heart, lungs and circulation is the provision of oxygen (and other nutrients) to the various organs and tissues of the body. During this process, carbon dioxide and other metabolic waste products are removed. The rate of supply and removal should match the specific metabolic requirements of the individual tissues. This requires adequate oxygen uptake in the lungs, global matching of delivery and consumption, and regional control of the circulation.

Oxygen transport of the Respiratory System

Oxygen transport Cycle Labeled Diagram

Failure to supply sufficient oxygen to meet the metabolic requirements of the tissues is the cardinal feature of circulatory failure or ‘shock’, and optimisation of tissue oxygen delivery and consumption is the goal of resuscitation. Atmospheric oxygen moves down a partial pressure gradient from air, through the respiratory tract, from alveoli to arterial blood and is then transported in the circulation to the capillary beds and cells, diffusing into the mitochondria and being utilised at cytochrome a 3 Clinically important points to note in the management of a critically ill patient are that:

The movement of oxygen from • the left ventricle o the systemic tissue capillaries is referred to as oxygen delivery (DO 2), and is the product of cardiac output (flow) and arterial oxygen content (CaO

2). The latter is calculated from CaO2 = Hb × arterial oxygen saturation of haemoglobin (SaO2) × 1.34. By increasing cardiac output, arterial oxygen saturation or haemoglobin concentration, DO 2 will be increased.

• The regional distribution of oxygen delivery is also vital. If skin and muscle receive high blood flows but the splanchnic bed does not, the gut will become hypoxic even if overall DO 2 is high.
• The movement of oxygen from tissue capillary to cell occurs by diffusion and depends on the gradient of oxygen partial pressures, diffusion distance and the ability of the cell to take up and use oxygen. Thus microcirculatory, tissue diffusion and cellular factors, as well as DO 2, influence the oxygen status of the cell.

Pharmacokinetics and pharmacodynamics

Pharmacokinetics and pharmacodynamics - Pharmacokinetics of antimicrobial agents determine whether adequate concentrations are obtained at the primary site of infection and likely areas of dissemination. Septic patients often have poor gastrointestinal absorption, so the preferred initial route of therapy is intravenous. Knowledge of anticipated antimicrobial drug concentrations at sites of infection is critical. For example, achieving a ‘therapeutic’ blood level of gentamicin is of little practical use in treating meningitis, as CSF penetration of the drug is severely limited. Knowledge of routes of elimination is also critical in antimicrobial therapy; for instance, a urinary tract infection is more appropriately treated with a drug that is excreted unchanged in the urine than one which is fully eliminated by hepatic metabolism.

Pharmacodynamics vs Pharmacokinetics

Pharmacokinetics and pharmacodynamics parameters

Pharmacodynamics describes the relationship between antimicrobial concentration and microbial killing. For many agents, antimicrobial effect can be categorised as concentration-dependent or time-dependent. The concentration of antimicrobial achieved after a single dose is illustrated in Figure 6.15. The maximum concentration achieved is C max and the measure of overall exposure is the area under the curve (AUC).

The efficacy of antimicrobial agents whose killing is concentration-dependent (e.g. aminoglycosides) increases with the amount by which C max exceeds the minimuminhibitory concentration (C max :MIC ratio). For this reason, it has become customary to administer aminoglycosides (e.g. gentamicin) infrequently at high doses (e.g. 7 mg/kg) rather than frequently at low doses. This has the added advantage of minimising toxicity by reducing the likelihood of drug accumulation. Conversely, the β-lactam antibiotics, macrolides and clindamycin exhibit time-dependent killing, and their efficacy depends on C max exceeding the MIC for a certain time (which is different for each class of agent). This is reflected in the dosing interval of benzylpenicillin, which is usually given every 4 hours in severe infection (e.g. meningococcal meningitis), and may be administered by continuous intravenous infusion. 

For other antimicrobial agents the relationships between MIC, C max and AUC are more complex and often less well understood. With some agents bacterial inhibition persists after antimicrobial exposure (post-antibiotic and post-antibiotic sub-MIC effects).

Antimicrobial resistance

Antimicrobial resistance - Microorganisms have evolved in the presence of antibiotics, which are antimicrobial agents produced naturally by bacteria and fungi. They have therefore developed multiple resistance mechanisms (categorised in Fig. 6.14) to all classes of antimicrobial agent (antibiotics and their derivatives). Resistance may be an innate property of a microorganism (intrinsic resistance) or may be acquired, by either spontaneous mutation or horizontal transfer of genetic material from another organism. For some agents, e.g. penicillins, a degree of resistance occurs in vivo when the bacterial load is high and the molecular target for the antimicrobial is down-regulated (an ‘inoculum effect’).

Antimicrobial Resistance

Antimicrobial Resistance

The mecA gene encodes a low-affinity penicillin-binding protein, which confers resistance to meticillin and other penicillinase-resistant penicillins in Staph. aureus. It is common for plasmids to encode resistance to multiple antimicrobials, which may be transferred horizontally. Extended spectrum â-lactamases (ESBL) are encoded on plasmids, which are transferred relatively easily between bacteria including Enterobacteriaceae. Plasmid-mediated carbapenemases have been detected in strains of Klebsiella pneumoniae. Glycopeptide resistance in enterococci is also transferred on mobile genetic elements. Strains of MRSA have been described that exhibit intermediate resistance to glycopeptides, through the development of a relatively impermeable cell wall (GISA).

Factors implicated in the emergence of antimicrobialresistance include the inappropriate use of antibiotics when not indicated (e.g. in viral infections) inadequate dosage or treatment duration, excessive use of broad- spectrum agents, and use of antimicrobials as growth-promoters in agriculture. However any antimicrobial use exerts a selection pressure that favours the development of resistance. Combination antimicrobial therapy may reduce the emergence of resistance. This is recommended in treatment of patients infected with HIV, which is highly prone to spontaneous mutation (p. 406). 

Despite use of combination therapy for M. tuberculosis, multidrug-resistant TB (MDR-TB, resistant to isoniazid and rifampicin) and extremely drug-resistant TB (XDR-TB,  resistant to isoniazid and rifampicin, any fluoroquinolone, and at least one injectable antimicrobial antituberculous agent) have been reported worldwide and are increasing in incidence (p. 693).