ephedrine, but usually for their effects on the central nervous system (narcolepsy, attention deficit in children). (For a general account of amphetamine, see p. 193)
Phenylephrine has actions qualitatively similar to noradrenaline but a longer duration of action, up to an hour or so. It can be used as a nasal decongestant (0.25-0.5% solution), but sometimes irritates. In the doses usually given, the central nervous effects are minimal, as are the direct effects on the heart. It is also used as a mydriatic and briefly lowers intraocular pressure.
Nasal and bronchial decongestants (vasoconstrictors) are widely used in allergic rhinitis, colds, coughs and sinusitis, and to prevent otitic barotrauma, as nasal drops or nasal sprays. All the sympathomimetic vasoconstrictors, i.e. with a effects, have been used for the purpose, with or without an antihistamine (Hj-receptor), and there is little to choose between them. Ischaemic damage to the mucosa is possible if they are used excessively (more often than 3-hourly) or for prolonged periods (> 3 weeks). The occurrence of rebound congestion is also liable to lead to overuse. The least objectionable drugs are ephedrine 0.5% and phenylephrine 0.5%. Xylometazoline 0.1% (Otrivine) should be used, if at all, for only a few days since longer application reduces the ciliary activity and will lead to rebound congestion. Naphazoline and adrenaline should not be used, and nor should blunderbuss mixtures of vasoconstrictor antihistamine, adrenal steroid and antibiotics. Oily drops and sprays, used frequently and long-term, may enter the lungs and eventually cause lipoid pneumonia.
It may sometimes be better to give the drugs orally rather than up the nose. They interact with antihypertensives and can be a cause of unexplained failure of therapy unless enquiry into patient self-medication is made. Fatal hypertensive crises have occurred when patients treated for depression with a monoamine oxidase inhibitor have taken these preparations.
Definition. Shock is a state of inadequate capillary perfusion (oxygen deficiency) of vital tissues to an extent that adversely affects cellular metabolism (capillary endothelium and organs) causing malfunction, including release of enzymes and vasoactive substances,6 i.e. it is a low flow or hypoperfusion state.
The cardiac output and blood pressure are low in fully developed cases. But a maldistribution of blood (due to constriction, dilatation, shunting) can be sufficient to produce tissue injury even in the presence of high cardiac output and arterial blood pressure (warm shock), e.g. some cases of septic shock.
The essential element, hypoperfusion of vital organs, is present whatever the cause, whether pump failure (myocardial infarction), maldistribution of blood (septic shock) or loss of total intravascular volume (bleeding or increased permeability of vessels damaged by bacterial cell products, burns or anoxia). Function of vital organs, brain (consciousness, respiration) and kidney (urine formation) are clinical indicators of adequacy of perfusion of these organs.
Treatment may be summarised:
• Treatment of the cause: bleeding, infection, adrenocortical deficiency
• Replacement of any fluid lost from the circulation
• Perfusion of vital organs (brain, heart, kidneys) and maintenance of the mean blood pressure.
Blood floxv (oxygen delivery) rather than blood pressure is of the greatest immediate importance for the function of vital organs. A reasonable blood pressure is needed to ensure organ perfusion but peripheral vasoconstriction may maintain a normal mean arterial pressure despite a very low cardiac output. Under these circumstances, blood flow to vital organs will be inadequate and multiple organ
6 In fact, a medley of substances (autacoids), kinins, prostaglandins, leukotrienes, histamine, endorphins, serotonin, vasopressin, has been implicated. In endotoxic shock, the toxin also induces synthesis of nitric oxide, the endogenous vasodilator, in several types of cells other than the endothelial cells which are normally its main source.
failure will ensue unless the patient is resuscitated adequately.
The decision how to treat shock depends on assessment of the pathophysiology:
• whether cardiac output, and so peripheral blood flow, is inadequate (low pulse volume, cold-constricted periphery)
• whether cardiac output is normal or high and peripheral blood flow is adequate (good pulse volume and warm dilated periphery), but there is maldistribution of blood
• whether the patient is hypovolaemic or not, or needs a cardiac inotropic agent, a vasoconstrictor or a vasodilator.
In poisoning by a cerebral depressant or after spinal cord trauma, the principal cause of hypotension is low peripheral resistance due to reduced vascular tone. The cardiac output can be restored by simply tilting the patient head-down and by increasing the venous filling pressure by infusing fluid. Vasoactive drugs (noradrenaline, dobutamine) may be beneficial.
In central circulatory failure (cardiogenic shock, e.g. after myocardial infarction) the cardiac output and blood pressure are low due to pump failure; myocardial perfusion is dependent on aortic pressure. Venous return (central venous pressure) is normal or high. The low blood pressure may trigger the sympathoadrenal mechanisms of peripheral circulatory failure summarised below.
Not surprisingly, the use of drugs in low output failure due to acute myocardial damage is disappointing. Vasoconstriction (by an a-adreno-ceptor agonist), by increasing peripheral resistance, may raise the blood pressure by increasing afterload, but this additional burden on the damaged heart can further reduce the cardiac output. Cardiac stimulation with a (3,-adrenoceptor agonist may fail; it increases myocardial oxygen consumption and may cause an arrhythmia. Dobutamine, dopexamine or dopamine offer a reasonable choice if a drug is judged necessary; dobutamine is preferred as it tends to vasodilate, i.e. it is an 'inodilator'. A selective phosphodiesterase inhibitor such as enoximone may also be effective, unless its use is limited by hypotension.
If there is bradycardia (as sometimes complicates myocardial infarction), cardiac output can be increased by vagal block with atropine, which accelerates the heart rate.
Septic shock is severe sepsis with hypotension that is not corrected by adequate intravascular volume replacement. It is caused by lipopolysaccharide (LPS) endotoxins from Gram-negative organisms and other cell products from Gram-positive organisms; these initiate host inflammatory and procoagulant responses through the release of cytokines, e.g. interleukins, and the resulting diffuse endothelial damage is responsible for many of the adverse manifestations of shock, including multiorgan failure. First, there is a peripheral vasodilatation from activation of nitric oxide by LPS and cytokines, with eventual fall in arterial pressure. This initiates a vigorous sympathetic discharge that causes constriction of arterioles and venules; the cardiac output may be high or low according to the balance of these influences. There is a progressive peripheral anoxia of vital organs and acidosis. The veins (venules) dilate and venous pooling occurs so that blood is sequestered in the periphery and effective circulatory volume falls because of this, and of fluid loss into the extravascular space from endothelial damage caused by bacterial products.
When septic shock is recognised, appropriate antimicrobials should be given in high dose immediately after the taking of blood cultures (see p. 237). Beyond that, the prime aim of treatment is to restore cardiac output and vital organ perfusion by accelerating venous return to the heart and to reverse the maldistribution of blood. Increasing intravascular volume will achieve this, guided by the central venous pressure to avoid overloading the heart. Oxygen is essential as there is often uneven pulmonary perfusion.
After adequate fluid resuscitation has been established, inotropic support is usually required. Noradrenaline is the inotrope of choice for septic shock: its potent oc-adrenergic effect increases the mean arterial pressure and its modest [3, effect may raise cardiac output, or at least maintain it as the peripheral vascular resistance increases. Dobutamine may be added further to augment cardiac output.
Some clinicians use adrenaline, in preference to noradrenaline plus dobutamine, on the basis that its powerful a and (3 effects are appropriate in the setting of septic shock; it may exacerbate splanchnic ischaemia and lactic acidosis.
Hypotension in (atherosclerotic) occlusive vascular disease is particularly serious, for these patients are dependent on pressure to provide the necessary blood flow in vital organs whose supplying vessels are less able to dilate. It is important to maintain an adequate mean arterial pressure, whichever inotrope is selected.
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