Propranolol

Generic propranolol 20mg mastercard

The context-sensitive half-life is a concept to describe how the duration of infusion (the context) alters the effective elimination half-life of the drug heart disease month buy propranolol. The same effect is seen with volatile anaesthetic agents, as described in Chapter 29, with the longer duration of inhalation leading to slower elimination by the lungs. These may involve physicochemical, pharmacodynamic or pharmacokinetic interactions with biochemical and physiological systems of the body. The main, intended action of a drug may not be the only effect that the substance has on the body, and there may be multiple modes of action. For example, many drugs interact with more than one type of receptor, and some may alter the pharmacokinetics of co-administered drugs by enzyme induction or inhibition. Charge neutralisation this mode of action is typified by the action of the antacid drugs. Citric acid and sodium citrate act as a buffer-pair, reducing the concentration of hydrogen ions and increasing stomach pH. Calcium bicarbonate is also an effective antacid, but the reaction produces carbon dioxide, which can cause abdominal distension and flatulence. To avoid this problem sodium citrate is preferred preoperatively to reduce the risk of aspirationinduced lung damage in high-risk patients requiring general anaesthesia. Sodium citrate should not be used long-term because of the high sodium load: antacid drugs for prolonged use should not be absorbed. Aluminium hydroxide preparations are relatively insoluble and longer-lasting, so come closest to ideal, although care should be taken in renal failure. Another example of charge neutralisation is the use of protamine in reversing the effects of heparin (see Chapter 41). Protamine is a fish spermatozoal protein that is strongly basic due to a high arginine content, and carries a high density of positive charge; heparin is acidic and carries a negative charge. The combination of Physicochemical mechanisms these mechanisms are generally non-specific, and depend on the physicochemical properties of a drug including its molecular size, shape, whether it is a weak acid or weak base, the pKa of its constituent groups and its lipid and water solubility. Non-specific physicochemical mechanisms of action include: r Charge neutralisation (pH effects) r Osmotic effects r Adsorption r Chelation Fundamentals of Anaesthesia, 4th edition, ed. Chapter 28: Mechanisms of drug actions 579 protamine and heparin produces a complex that has no anticoagulant effect. Pharmacodynamic mechanisms Many drugs exert their effects through an interaction with specific and selective sites on receptors. Receptors are large proteins that are associated with cellular structures such as cell membranes, cytoplasm, intracellular membranes or nuclear material. The selectivity arises from the 3D chemical configuration of the drug, which matches a site on the relevant protein and allows binding to take place. This type of action is characterised by a lock-and-key mechanism involving different chemical forces that allow the drug first to approach its active site and then to fit into a selective binding area. Initial attraction may be by ionic forces, but stabilisation is due to van der Waals interactions once the drug is in close proximity to its selective binding site. Mannitol exerts an osmotic effect in the plasma, like glucose, which leads to expansion of the extracellular volume and reduction of blood viscosity. It also has a diuretic effect, because it is freely filtered and minimally reabsorbed. Large volumes of mannitol must be avoided to prevent impaired tubular function as the result of the high plasma osmolality. Adsorption Non-specific adsorption of drugs to activated charcoal allows the latter to be used in the treatment of drug overdose by effectively removing free drug from the stomach. Charcoal is not always effective and is not useful in lithium, cyanide, iron, ethanol or methanol poisoning. Chelation and inclusion complexes Heavy metal ions such as lead, arsenic and copper can effectively be removed by using chelating agents. These agents have multiple oxygen, sulphur or nitrogen atoms that form coordinate bonds (where the ligand contributes both electrons) with the metal ion. An ideal chelating agent will be water-soluble, not undergo biotransformation, have a low affinity for calcium and form nontoxic metal complexes that can readily be excreted. They present a hydrophilic outer surface and an internal hydrophobic cavity that can trap other molecules by forming an inclusion complex. Modified cyclodextrins are used extensively for masking odours and as drug delivery systems for poorly water-soluble drugs. Sugammadex is a -cyclodextrin reversal agent that selectively forms an inclusion complex with rocuronium and less so with vecuronium but not with benzylisoquinolinium muscle relaxants. This produces effective reversal of rocuronium effects from any depth of neuromuscular blockade without the unwanted effects of widespread inhibition of acetylcholinesterase. The most important neurotransmitter-associated receptors are ligand-gated ion channels and G-protein-coupled receptors. Other membrane-dependent transduction mechanisms include tyrosine kinase and guanylyl cyclase-coupled receptors. Ligand-gated ion channels Ion channels that are opened as a result of binding of neurotransmitters are known as ligand-gated ion channels. They must be distinguished from ion channels that are opened as a result of a change in membrane potential (voltage-gated channels). Many of the drugs we use interfere with ligand-gated ion channels that mediate very rapid transmission of information through the central and peripheral nervous systems. Neurotransmitters either depolarise the postsynaptic membrane, allowing forward transmission of electrical signals, or hyperpolarise the membrane, inhibiting such signals. The name cys-loop comes from the fact that in the extracellular N-terminal region there are two disulphide cysteine bridges, forming a looped structure. Depolarising blockers, such as suxamethonium, bind to the same site as the natural transmitter acetylcholine and cause opening of the ion channel by inducing similar conformational changes, although channel opening time is increased. Suxamethonium persists longer in the synaptic cleft than acetylcholine because it is not a substrate for acetylcholinesterase. As a result the receptor cannot return to its resting conformation but becomes desensitised: it no longer responds to the agonist, and neuromuscular blockade ensues. A similar picture is seen in the presence of irreversible inhibition of acetylcholinesterase by organophosphates: acetylcholine itself induces paralysis. As discussed below, these neuronal nicotinic receptors are sensitive to the effects of certain general anaesthetic agents. Subunit stoichiometry depends on anatomical location, but 1:2:2 and 2:2:1 are most common. The benzodiazepine binding site requires both and subunits to be present, whereas etomidate binds with higher affinity to receptors with a 2 or 3 subunit. There are several types of serotoninergic receptors, but only type 3 are ionotropic; the others are all G-protein-coupled receptors. All ionotropic glutamate receptors are equally permeable to Na+ and K+ but have a particularly high permeability to the divalent cation, Ca2+, unlike the pentameric excitatory channels. Ionotropic purinergic receptors: P2X subtypes Receptors of this family form cation channels that are equally permeable to Na+ and K+ but also to Ca2+. The analgesic property of pentobarbital is thought to be due to inhibition of P2X receptors in the dorsal root ganglia. These ionotropic purinergic receptors are not to be confused with G-protein-coupled receptor forms of purinergic receptors: adenosine receptors (P1) and P2Y subtypes. The quaternary structure is such that these helices cluster together, held in the correct alignment by interactions with extracellular/intracellular domains. When a ligand binds, these helices twist in relation to each other, inducing a conformational change that is transmitted to the domain that is associated with G-protein coupling. The ligand binding site is determined by the composition of the second and third extracellular loops, whereas the second and third intracellular loops are associated with G-protein binding. G proteins are associated with the inner leaflet of the cell membrane and are not always associated with receptors. When the ligand binds, a conformational change occurs that increases the likelihood of the receptor becoming associated with its particular G protein. Essentially the receptor can exist in a number of states, which differ in their affinity for agonist, antagonist or inverse agonist.

Discount propranolol 80 mg fast delivery

All three groups of calcium antagonist reduce systemic vascular resistance and central venous pressure by vasodilatation coronary heart program purchase propranolol amex. This vasodilatation is more pronounced in the arterial system, and as it is combined with a slight negative inotropic effect blood pressure falls. The reduction in afterload and contractility reduces myocardial workload and oxygen requirement. All calcium antagonists cause coronary vasodilatation, but this is only of clinical relevance in coronary artery spasm. Calcium antagonists may also interfere with noncardiac calcium channels, affecting, for example, neuromuscular blockade and insulin secretion. This lengthening of the action potential makes them appropriate for tachyarrhythmias, especially re-entry supraventricular tachycardias and others of atrial origin. Papaverines have relatively little effect on vasomotor tone, but the reduction in contractility is more marked than with the other calcium channel blockers. It is used as an antiarrhythmic drug and for the treatment of angina and hypertension. The net effect is an increase in calcium ion availability in the cell for contraction. Clinically this mainly affects vascular tone, causing peripheral vasodilatation primarily on the arterial side, and so reduces afterload. The resultant drop in blood pressure results in a partial compensatory increase in heart rate and cardiac output. They also cause coronary vasodilatation, but this is not generally of clinical benefit. Nimodipine acts preferentially on cerebral arteries and is used to prevent vascular spasm after subarachnoid haemorrhage. The positive inotropic effect is greater than that of the cardiac glycosides and there is little chronotropic activity. Coronary vascular resistance is also reduced, but this does not appear to cause coronary steal. These agents are used in the short-term treatment of severe congestive cardiac failure when other measures have failed. They work synergistically with -adrenoceptor agonists, and can work when the latter used alone have failed. Phosphodiesterase inhibitors Selective phosphodiesterase inhibitors are used for their inotropic and vasodilator properties. In the myocardium, this increases the influx of calcium through the slow calcium channels of the sarcolemma by increasing both the number of channels open and the duration of the open state. It may potentially cause hypotension because of vasodilatation, necessitating close monitoring. Eighty per cent is eliminated unchanged in the urine, and it is therefore greatly influenced by decreases in renal function. In severe myocardial failure, glomerular filtration rate is often reduced and so half-life is increased from the normal 1 hour to several hours. Ventricular tachycardias and ectopic beats have been observed in some patients who have received enoximone. The propensity to cause hypotension (due to vasodilatation) necessitates monitoring of blood pressure. Enoximone is metabolised in the liver, producing a mixture of active and inactive metabolites, and has a half-life of about 4 hours. These drugs act by selective agonism at the imidazoline subtype 1 receptor (I1) in the rostral ventrolateral pressor area and ventromedial depressor areas of the medulla oblongata. This area is responsible for sympathetic activity, and an agonist effect at I1 receptors results in a reduction of general sympathetic nervous system activity which produces the desired effect. An example from this group is moxonidine, a centrally acting antihypertensive agent for mild to moderate hypertension. It may exacerbate cardiac conduction defects and should be withdrawn slowly over a 2-week period. Caution is necessary when administering moxonidine with benzodiazepines, as the sedative effects of the latter become enhanced. These three activities produce a rise in intravascular volume and vasomotor tone with the resultant increase in blood pressure. They are particularly effective when renin levels are raised, such as when sympathetic tone is increased. The first site of interference in this cascade is by antagonism of the -adrenoceptors responsible for renin secretion. The protein left in the efferent capillaries supplying the remainder of the nephron is therefore more dilute and has a lower oncotic pressure, which reduces reabsorption from the nephron. Subsequently more filtrate enters the loop of Henle, which is the primary site of action of the loop diuretics. In congestive cardiac failure, the venodilatation reduces preload before any diuretic effect is seen. Loop diuretics work as antihypertensives by reducing both blood volume and vascular tone. The vascular effects may be mediated by interference with prostaglandin E2 and I2 degradation. Hydrogen ions are also excreted in exchange for some of the potassium, and bicarbonate concentration increases. Patients on loop diuretics are therefore at risk of hypokalaemia and metabolic alkalosis. Loop diuretics are highly protein-bound, and therefore do not readily pass through the glomerular membrane. They are actively secreted into the proximal convoluted tubule (via the organic acid transport system) and then travel along the tubule to the luminal membrane of the loop of Henle. Interference with sodium reabsorption in the renal tubule causes increased sodium loss, and the sodium takes water with it. This interferes with the generation of the interstitial hypertonicity which is used by the collecting duct to reabsorb water. A smaller effect is due to the increased delivery of filtrate to the distal tubule. They are medium-efficacy diuretics, causing up to 10% of sodium and water in the filtrate to be excreted. More sodium reaches the distal tubules, and this results in high potassium loss in the same way as with the loop diuretics, but because this is the main mode of thiazide action potassium loss is a much greater problem. Magnesium excretion is increased, but calcium and uric acid excretion are reduced.

Buy propranolol without prescription

Having decided upon intubation coronary heart 55 order genuine propranolol on-line, controlled ventilation should be used, and commonly a non-depolarising relaxant, opioid, vapour combination is used for the maintenance of anaesthesia. Extubation should be undertaken in the head-down lateral position after adequate pharyngeal suction. There are two choices for timing of this event: while the patient is still deep, or after protective reflexes have returned. The potential for transmission of prion disease by surgical and anaesthetic instruments is discussed in Chapter 5. Following post-tonsillectomy haemorrhage, the patient will usually be pale, tachycardic and sweaty. Intravenous resuscitation is essential before induction, and two different techniques of anaesthesia have been recommended. In both situations the patient should be placed head-down, in left lateral position, with suction to hand. Following preparation of all equipment a choice may be made between intravenous or gaseous induction. Alternatively, a gaseous induction of vapour and oxygen may be employed, using suction as necessary and enough time to achieve a plane of anaesthesia deep enough to permit laryngoscopy and intubation. Some authorities recommend the emptying of swallowed blood from the stomach with a nasogastric tube before extubation, which would appear wise. Middle ear surgery Middle ear surgery has one main requirement which differentiates it from other surgical procedures. This is the need to control blood loss in order to provide the surgeon with the best possible view down the microscope. Lidocaine spray to the Tonsillectomy Anaesthesia for tonsillectomy with or without adenoidectomy requires defence of the shared airway from blood and debris. This necessarily involves endotracheal intubation Chapter 6: the surgical insult 135 larynx has been advocated before intubation to reduce the response to the presence of the tube, as has the use of alfentanil with induction. Arterial hypotension is often requested, and provided there are no contraindications this may be achieved by the use of sodium nitroprusside by controlled infusion or -blockade (esmolol is a suitable choice). Inspired oxygen concentration should be increased and a slight head-up tilt will reduce bleeding by aiding venous drainage. It has been suggested that avoidance of nitrous oxide is beneficial to avoid pressure rises in the middle ear as it diffuses in. An antiemetic drug should be administered during the procedure, as nausea from disturbance of labyrinthine function is frequent and postoperative vomiting is particularly undesirable. This can usually be achieved by smooth anaesthesia with muscle relaxation and controlled ventilation to achieve mild hypocapnia, whether via a tracheal tube or a laryngeal mask. The latter is preferable, because of the lack of intubation pressor response or laryngeal spasm and coughing on extubation. Local anaesthesia is also an alternative for cataract surgery, but has a higher failure rate, more complications and less predictable reduction of intraocular pressure. Patients who cannot lie flat without coughing or distress, or who cannot communicate because of language, deafness or dementia, cannot safely have their cataract surgery under local anaesthesia. Tracheostomy the majority of elective tracheostomies are performed on intensive care patients following long-term oral intubation. In this instance anaesthesia is usually maintained by the use of opioid agents with or without volatile supplementation and muscle relaxants as required to facilitate controlled ventilation. The critical element of the procedure is to avoid completely withdrawing the existing endotracheal tube before the surgeon has gained control of the airway with the tracheostomy tube and secured it in place. If this is not achievable, the original tube can be re-advanced and oxygenation maintained. If the endotracheal tube has been removed without securing the tracheostomy tube correctly, a potentially dangerous situation develops which may be fatal. Transfer of connecting tubing from old to new tube should be as quick as possible to avoid desaturation. Emergency tracheostomy is a difficult and hazardous procedure best performed under local anaesthesia. Squint surgery the majority of patients for squint surgery are children, though occasional adults may present for cosmetic corrections. This operation is difficult to carry out with local anaesthesia because of the age of the patient and the manipulations necessary in the orbit. General anaesthesia should be carried out with the airway maintained by either a laryngeal mask or a tracheal tube. All patients having squint surgery should receive a weight-related dose of a vagolytic such as glycopyrrolate to obtund the oculocardiac reflex, which can cause severe bradycardia on traction of the extraocular muscles. Tracheal tubes in small children restrict the cross-sectional area of the airway with a consequent increase in resistance to gas flow (resistance is inversely proportional to the 4th power of the radius). After extubation, the smallest amount of laryngeal or tracheal oedema can cause major falls in oxygen saturation. Laryngeal spasm at extubation causes sudden dramatic falls in saturation, and the facilities for reintubation with a muscle relaxant should be immediately to hand. The tracheal tube used during the surgery should not be disposed of until the patient leaves the recovery room. Ophthalmic surgery Cataract surgery Cataracts may be congenital, traumatic, steroid- or radiation-induced, or degenerative. In degenerative cataracts there will also be other medical conditions associated with ageing. While people with diabetes have no more cataracts than the general population, they tend to present earlier and so there seems to be a preponderance of diabetic patients presenting for cataract surgery. Steroidinduced cataracts present in patients taking long-term steroids for other conditions, particularly eczema or asthma, which should be taken into account. Retinal surgery Retinal detachments present sporadically, but are not usually so urgent that they have to be done immediately on presentation. The patients are often hypertensive, though whether this is cause or effect is debatable. A vagolytic agent should be used to prevent the oculocardiac reflex during surgical manipulation of the globe. Occasionally the surgeon may wish to introduce a gas bubble between the vitreous and retina to tamponade the retina. If this is planned then nitrous oxide should be avoided or turned off as soon as the decision is made. Nitrous oxide diffuses into closed gas-filled spaces and increases the volume of the bubble or, if the area has low compliance, the pressure will rise. While this may be acceptable during the procedure, it will diffuse out in the postoperative period and the pressure or volume will reduce, reducing the tamponade effect. The airway is usually maintained with a tracheal tube, though the laryngeal mask will avoid the pressor response to the presence of the tube and so may avoid the need for active reduction of blood pressure. A pharyngeal pack is essential to absorb blood that trickles down from the nasopharynx. Oral and maxillofacial surgery Dental extraction Simple dental extraction demands good control of a shared airway and a degree of understanding between anaesthetist and dentist. The majority of dental extractions are carried out on a day-case basis unless there is significant coexisting disease. There is still some debate as to whether the traditional sitting position or the supine position is better. The latter provides some protection against fainting on induction of anaesthesia, but encourages regurgitation of stomach contents. Induction of anaesthesia may be by inhalation or intravenous injection, but in both cases venous access should be obtained first. The sudden falls in blood pressure associated with propofol tend to limit its use in the dental chair, particularly in the sitting position. There is no need for intravenous opioids, and simple analgesics are adequate in the postoperative period. Many children prefer inhalational induction, which should be with halothane or sevoflurane in a nitrous oxide/oxygen mixture. Isoflurane has too pungent a smell and enflurane causes too much coughing and salivation to be useful. Once adequate anaesthesia has been established, the mouth is opened and a pack inserted between the mouth cavity and the pharynx, separating the nasal airway from the oral airway.

Discount propranolol 20 mg

The results of such a comparison may be expressed in three different ways heart disease leading cause of death buy propranolol online, as a risk difference, a relative risk or an odds ratio. This test is used to test the relationship between the row and column variables in a contingency table. It provides an estimate of how significant the differences observed between column and row variables in the contingency table are. In this case H0 is that there is no difference between groups, and therefore both rows are samples from the same population. Some examples of such studies (with the basic question to be asked of the results in brackets) might be: r Incidence of prostatic cancer in two groups: smokers and non-smokers (is smoking a risk factor for prostatic cancer The expected values are calculated as if there was no difference between the groups (rows). The observed numbers in each category for each group are shown outside the brackets. If there were no difference between groups, all of the patients could be considered as one big group of 30 patients. In such a case equal numbers would be expected in each of the outcome columns for each group. The expected values would then be those bracketed in the contingency table, and using these the 2 value can be calculated. Using the 2 value, a P-number can be obtained by looking it up in the appropriate table for 2. This means that the differences between the groups shown in the contingency table are significant. Chapter 43: Clinical trials and basic statistics 775 Risk Risk can be defined as the probability of a condition occurring in a sample group. In such a case there may be a positive risk difference between the control group (r2 = 0. Relative risk Relative risk is the ratio of the risk in the treated group to the risk in the untreated group. Such tests do not perform perfectly, and in some cases the condition may be missed (false negatives) while in others the test may give a false positive result. Out of the 100 subjects, 20 test positive and 80 test negative, but only 16 are subsequently proved to have the condition. Sensitivity Sensitivity is a measure of how good a test is at correctly identifying patients who have a condition, since the test will not detect all cases with the condition, but will produce a number of false-negative results. Specificity Specificity describes how good a test is at confirming the absence of a condition in patients who do not have the condition, since the test will not be negative in all patients without the condition, but will produce a number of false-positive results. Given a positive result in the test, what is the likelihood that a person has the condition compared to the likelihood of obtaining a positive result in somebody free from the condition Given a positive result, a person is 15 times as likely to have diabetes as to be free from the condition. Consider investigating the postoperative analgesic requirements for patients from k different cities, with n patients in each group. Or is the variation in the mean values simply due to individual variation rather than geographical variation The null hypothesis is that no difference exists and the groups are all from the same population. This test is known as one-way analysis of variance because a single factor is being tested for. How good is the test at predicting absence of the condition when the result is negative This test is an extension of the Wilcoxon rank sum test, and is not described further here. If a relationship is found this is used as a model, and predictions can be made using this model. The simplest relationship mathematically is a linear one, and plotting a graph of one variable against the other will produce a straight-line graph. This is quantified by measuring these variables in a sample of the population and calculating their correlation coefficient, r. If two variables x and y are measured in a group of individuals they can be plotted against each other to produce a scatter plot. Correlation describes a purely mathematical relationship and does not imply any causal relationship. For example, random fasting blood sugar levels may show some degree of correlation with shoe size. This does not mean that wearing Testing for correlation between two variables As in other statistical tests, when testing for correlation between two variables the null hypothesis (r = 0) is tested for and a P-number is determined from statistical tables. Calculation of the value of r is laborious and is commonly available in commercial software packages. Then find the differences between the coordinates of each data point (x, y) and the mean point (xm, ym). With normally distributed data, five points in a sample might Chapter 43: Clinical trials and basic statistics 779 give r = 0. Points to note about correlation: r the Pearson correlation coefficient is calculated for normally distributed variables. Linear correlation enables an observer to assess the degree of linear association between two variables but provides no further information upon which predictions can be made. Linear regression is used to mathematically model the relationship between two continuous variables by identifying the gradient and intercept of the best-fit line. Linear regression is used to define the best straight line fitting the points of the scatter diagram. Here it is assumed that one variable, x, is independent, and that the other variable, y, is dependent on x. By knowing the coefficients a and b, any value of y can be calculated for a given value of x using the regression line. Performing linear regression analysis In order to calculate the regression coefficients a and b, a method of least squares is used. This method selects the best straight line, which minimises the sum of the vertical distance of each point from the regression line (the sum of the residuals). Certain assumptions are made when using this method: r There is a linear relationship between x and y. Calculation of the gradient (b) and the intercept (a) is usually performed on readily available software. Goodness of fit for the regression line to the data is assessed by calculating a value for correlation coefficient squared (r2). This is the proportion of the variability in y due to the linear relationship with x. This means there should not be considerable variation between the outcome measures. Although systematic reviews and meta-analyses can be more powerful than individual studies they are still subject to their own sources of bias. Meta-analysis for a fixed effect most commonly results in a forest plot, which combines the results from a number of Trial centre Systematic reviews Many research studies may be performed over a period of decades before a particular treatment becomes employed routinely in clinical practice. Part of the process that may eventually result in a change in practice consists of reviewing the results from the different studies in order to reach a conclusion as to the efficacy of the intervention. Such a review can be misleading due to bias introduced by the selection of literature and differing methods of assessing results across studies.

40 mg propranolol with visa

The first breath generates a negative pressure of approximately 50 cmH2O cardiovascular ultrasound salary generic propranolol 40mg without prescription, drawing in about 80 mL of air and expanding the functional residual capacity. Exposure to oxygenated blood and reduced prostaglandin-E2 production stimulates ductal constriction, with functional closure in the majority of Fundamentals of Anaesthesia, 4th edition, ed. Preterm babies have a higher incidence of patent ductus arteriosus, and may require medical treatment with indomethacin, or surgical ligation. After the first breath, pulmonary venous blood returns to the left atrium, causing pressure in the left atrium to exceed that in the right. The valve-like foramen ovale closes, thus preventing deoxygenated blood from the right atrium crossing to the left. This muscle layer reduces considerably over the first few months and becomes thin-walled and elastic with little muscle by 6 months. However, immediately after birth, resistance in the pulmonary circuit is higher than in adults and the pulmonary arterioles remain very reactive. If the neonate becomes hypoxic, hypercapnic or acidotic, pulmonary vasoconstriction can lead to raised right-sided pressures and significant shunting through the foramen ovale, and reversion to a fetal-type circulation. Fetal and newborn circulation r the placenta supplies oxygen and nutrients to the In addition, calcium metabolism is immature in neonatal myocytes. Consequently there is a relatively flat Starling curve, and while inadequate preload is poorly tolerated, overloading results in early cardiac failure. The preterm neonate has significantly lower blood pressure than the term infant, and adult levels are not reached until adolescence. Autonomic innervation of the heart and blood vessels is incomplete in the newborn, with a relative lack of sympathetic supply. This is highlighted by the relatively small falls in blood pressure associated with high spinal blockade when using regional anaesthesia. Moreover, neonates are also less sensitive to the effects of catecholamines, needing much larger doses than older children or adults to achieve an increase in blood pressure and heart rate. Fetal circulation depends on three shunts to direct the best oxygenated blood to the upper body (foramen ovale), to bypass the underdeveloped liver (ductus venosus), and to bypass underdeveloped lungs (ductus arteriosus and foramen ovale). Blood flow through the liver increases, and the flow is decreased through the ductus venosus, which closes spontaneously. The heart the newborn heart consists of cardiac myofibrils that are poorly organised and lack the structured architecture of the mature heart. The increased ratio of connective tissue to contractile tissue compared to adults results in limitation in myocyte contractility and ventricular compliance. The fetal lung is filled with fluid essential for lung maturation and development. Irregular breathing movements are made in utero, which helps development of respiratory muscles, including the diaphragm and intercostal muscles. As full term approaches, catecholamines and triiodothyronine (T3) stimulate the reabsorption of pulmonary fluid by reversal of the chloride pump mechanism. Term babies may also be surfactantdeficient if they suffer severe acidosis or hypoxia, or if they are born to mothers with diabetes mellitus. The bronchial tree is fully developed at birth, in contrast to the alveoli, which continue to expand in both size and number, thus increasing the surface area of the lung by up to 25 times. Newborn infants have extremely compliant chest walls with compressible, horizontally aligned ribs. The diaphragm is the major muscle of ventilation in infancy, but can fatigue more easily in the neonate. In the first year of life, the percentage of type I, slow-twitch muscle fibres, which fatigue more slowly, increases from 10% to 25% (the adult level). In the weeks that follow, as chemoreceptors mature, the infant develops a predominantly hyperpnoeic response to hypoxia. In the developing embryo, the first nephrons form during week 5, are functional from week 8 and have reached their full complement by week 36. After this there is merely growth in size and number of cells in existing nephrons rather than new nephron formation. Renal blood flow comprises 5% of cardiac output at birth, but with reduced renal vascular resistance this increases to 20% by 1 month of age, with increasing flow to cortical areas. Renal function Hepatic function During intrauterine life, the fetus excretes fat-soluble unconjugated bilirubin via the placenta and maternal Chapter 24: Fetal and newborn physiology 535 liver. There is a physiological rise in bilirubin soon after birth, due to both an increased bilirubin load and immaturity of neonatal hepatic enzymes. Infants handle hepatically excreted drugs differently to older children and adults. Immature enzyme systems play a role, but so does the difference in blood supply to the liver. Infants receive a higher proportion of their hepatic blood supply via the portal vein than via the hepatic artery. Nociception Circumstantially, even the most preterm neonates respond to painful stimuli similarly to an adult, in terms of cardiovascular, stress and behavioural responses, but the presence or absence of pain as a conscious event can never be proven. Pain in the fetus and neonate Little can be inferred about the actual experience of pain in the fetus or neonate, or the attendant emotions, if any, relating to it. Given the impossible task of making judgements on the nature of pain perception in the fetus and neonate, the term nociception is more appropriate. Nociceptive pathways develop early in gestation, and even early in development they can produce complex protective responses to painful stimuli. Dorsal horn cells in the spinal cord have formed synapses with developing sensory neurones by 6 weeks gestation, and peripheral nerves migrate to the skin of the limbs by 11 weeks, achieving a density of nociceptive nerve endings similar to that of the adult by birth. The first appearance of transmitter vesicles is seen at 13 weeks gestation, and further synaptic connections and organisation of the dorsal horn structure continues up to 30 weeks. The fetal neocortex has a full complement of cells by 20 weeks, and thalamocortical tracts can be shown to synapse with dendritic processes of the cells in the neocortex by 24 weeks gestation. Myelination of some ascending nociceptive tracts is seen by 30 weeks, but thalamocortical radiations are not myelinated until 37 weeks and some nociceptive tracts are myelinated much later. However, lack of myelination does not imply lack of function: transmission of nerve impulses within the central nervous system still takes place in unmyelinated nerves, albeit at a reduced velocity. Noxious stimuli can produce both haemodynamic and stress responses in a human fetus as young as 18 weeks gestation, and these responses can be reduced by pretreatment with analgesic Thermoregulation Neonatal heat loss Neonates lose heat readily because of their higher ratio of surface area to body weight, and relative paucity of subcutaneous fat. Preterm infants have particularly thin skins, needing higher ambient temperatures and humidity. Heat loss occurs by evaporation, radiation, convection and to a lesser extent conduction, as well as by insensible losses such as through respiration. Infants are seldom able to increase heat production enough to compensate for heat loss, and newborns need to be nursed in a thermoneutral environment (at an ambient temperature that minimises oxygen consumption and heat loss). Unlike older children and adults, who generate heat involuntarily by shivering, newborns rely on nonshivering thermogenesis to increase their basal metabolic rate and thereby retain heat. This is a function of their unique brown fat, present in the first few weeks of life as an adaptive, protective entity. These specialised adipose cells are situated around the kidneys and adrenals, in the mediastinum and around the scapulae. They are abundant in mitochondria and have a rich blood and autonomic nerve supply. Overall, even the very preterm infant has complex interneuronal connections capable of integrated responses to tactile or nociceptive input. These infants show inconsistent responses to external stimuli, which may reflect the late functional connections of sensory afferents (particularly C fibres) within the spinal cord. Inconsistency of response to more complex noxious stimuli may also reflect the profound effects that conscious state and other external responses have on behaviour. Surgical stress in the neonate Although newborn infants often have short-lived behavioural and stress responses to noxious stimuli, there is evidence in this age group that surgical trauma or injury can have long-term consequences for sensory and pain behaviour in infancy. It is clear that in neonates repeated noxious stimuli produce hypersensitivity to further stimulation, and that poor operative analgesia can be associated with long-lasting hyperalgesia and behavioural changes such as irritability, reduced attentiveness and poor orientation, which may continue long after the expected duration of pain. The structure of the component atoms determines the type of bonds within the molecule.

Generic 20 mg propranolol mastercard

The incidence and clinical features of anaphylactic reactions during anesthesia in Australia cardiovascular system quiz for nurses 40mg propranolol mastercard. Difficult Airway Society guidelines for management of the unanticipated difficult intubation. After transfer of the patient from the anaesthetic room, the anaesthetist must ensure safe positioning of the patient and the re-establishment of appropriate monitoring while maintaining an appropriate depth of anaesthesia. This represents a period of significant risk for the patient, with the anaesthetist expected to complete a series of complex tasks simultaneously. Positioning Patient positioning can represent a significant challenge during anaesthesia. The aim of safe positioning is to provide optimal conditions for surgical access while minimising the risk of patient harm. The main hazards are related to the physiological changes associated with a change in posture and the effects of pressure. These effects are exaggerated by the loss of the normal homeostatic mechanisms which act to maintain organ perfusion during changes in position. For example reverse Trendelenburg positioning and abdominal compression in the prone position result in reduced venous return, reducing preload and cardiac output, which may result in significant hypotension. Interruptions in monitoring should be minimised during this period, with haemodynamic compromise anticipated and treated appropriately. Ventilation/perfusion mismatches may result in significant intrapulmonary shunting. Commonly injured nerves include the ulnar nerve, brachial plexus, lumbosacral roots, radial, sciatic and common peroneal nerves. Care must be taken to avoid excessive stretch or pressure on areas where nerves are susceptible to injury, such as the common peroneal nerve at the head of the fibula, the axillary plexus in the axilla and the ulnar nerve at the elbow. Where possible, joints should be maintained in a neutral position and pressure areas padded appropriately. Consideration should be given to individual patient risk factors, Fundamentals of Anaesthesia, 4th edition, ed. Chapter 3: Intraoperative management 47 for example obesity, peripheral vascular disease, pre-existing neuropathy, and their influence on potential nerve injury. It may be useful to assess preoperatively whether a patient can tolerate a particular position. The combination of pressure-related mechanical occlusion of the vasculature and shear forces results in the development of pressure areas which can progress to necrosis and ulceration. Pressure areas should be adequately padded, skin exposure to moisture minimised, and all sheets and pads smoothed out beneath the patient. Particular care should be paid when the patient is placed in the prone and Trendelenburg positions, and the eyes must be protected appropriately. Recovery from anaesthesia A high standard of monitoring should be maintained until the patient is fully recovered from anaesthesia. Clinical observations must be supplemented by the following monitoring devices: 1. The uninterrupted presence of a trained, competent and appropriately experienced anaesthetist is the most important component of this. Monitoring devices should be regarded as a supplement to clinical observation of signs such as the response to surgical stimulation, movement of the chest wall and breath sounds following intubation. Awareness during anaesthesia can be extremely distressing for patients with far-reaching consequences for their psychological wellbeing. Awareness may occur at any stage during an anaesthetic from induction to emergence. The prevention of awareness requires an appreciation of the causes and risk factors. For inhalational anaesthesia the depth of anaesthesia is related to the alveolar concentration of a volatile anaesthetic. This is further compounded by the lack of ability to directly monitor, in real time, the concentration of intravenous anaesthetic agents, in contrast to inhalational agents. This may be heralded by an increase in sympathetic nervous system activity, reflected by: r Tachycardia r Hypertension r Mydriasis r Sweating r Lacrimation these surrogate markers for depth of anaesthesia are unreliable under certain conditions. The use of depth of consciousness monitors does not prevent awareness but may reduce the risk in patients judged to be high risk. A regional block in this manner may be used to supplement a general anaesthetic technique and for postoperative analgesia. Inhalational anaesthesia the inhalational anaesthetics in common use produce loss of consciousness and to a variable degree muscle relaxation. Analgesia A balanced, multimodal approach to analgesia modified by surgical and patient factors is an important consideration for the anaesthetist. The provision of appropriate analgesia ameliorates the stress response to surgery and can help to reduce postoperative complications. Appropriate levels of analgesia also improve patient satisfaction and improve theatre productivity and patient flow. Intravenous anaesthesia Various agents have been employed for intravenous anaesthesia. Ketamine remains a widely used agent in the prehospital field and also in developing countries. An induction dose of propofol is followed by smaller bolus doses on an empirical basis. New concepts in pharmacokinetic modelling and computer technology have made these systems safe, reliable and user-friendly. The control of plasma levels is precise and rapid, with predictable onset and offset. Ventilation Ventilation may be maintained either spontaneously or by means of artificial ventilation. The mode for maintenance of ventilation will depend on surgical factors including the site, nature, extent and (to a degree) the likely duration of the operation. Patient factors influencing the type of airway selected will also determine the mode of ventilation. For example a spontaneously breathing, inhalational technique may be more suitable for relatively less stimulating body-surface surgery than for prolonged bodycavity surgery requiring muscle relaxation. Maintaining oxygenation to ensure adequate oxygen delivery to the tissues is essential, and consideration of the most appropriate mode to ensure this during surgery should form a part of preoperative assessment and planning. This may be provided by a face mask, supplemented with airway adjuncts if necessary or a supraglottic airway device. The depth of anaesthesia required to tolerate an endotracheal tube almost inevitably necessitates manual ventilation. Central drive is reduced by opioids and both inhalational and intravenous agents, and this may necessitate mechanical ventilation. In lighter planes of anaesthesia lung receptors may be irritated, resulting in coughing, which is more pronounced in the presence of irritant agents. Pulmonary mechanics (atelectasis, ventilation/perfusion mismatch and pre-existing pulmonary disease). Positioning has marked effects on the ability of the respiratory muscles to generate an adequate tidal volume. The effects are more pronounced in certain positions, as described earlier in this chapter. The development of alternative modes of ventilation including pressure support now allows for spontaneous breaths to be supported by the anaesthetic machine ventilator in theatre.

Cheap propranolol 40 mg on line

They are not present at birth blood vessels entering the cartilaginous epiphysis buy propranolol american express, and are thought to arise after exposure to foreign antigens in infancy. Some A2 and A2B people have low levels of anti-A1 in their serum, though this is rarely of clinical significance as it is not active at 37 C. Persons who are group O and are secretors secrete a precursor substance (H) in the saliva, group A secretors secrete A and H, and so on. Transfusion medicine Transfusion medicine involves the procurement, processing, testing and administration of blood and its components. It is also concerned with the prevention, investigation and treatment of transfusion-related complications. If the particular antibody is able to fix complement (IgM, IgG), then lysis occurs. If this occurs in vivo, an immediate (intravascular) haemolytic transfusion reaction occurs. D is the most important of the Rh antigens as it is more than 20 times more immunogenic than c, the next most important antigen. Because of the RhD testing of all donors and recipients, and immunoprophylaxis with anti-D during pregnancy and at delivery, the relative frequency of antiD compared with other Rh antibodies has declined significantly in recent years. Red cell units are still labelled RhD-positive or negative, but a proportion will also have a Rh genotype label. The reason for this is to indicate a lack of certain antigens (c and e in the examples given); these units are, therefore, suitable for patients whose serum contains the corresponding antibodies. There is generally a shortage of O RhD-negative blood due to high demand for universal usage in emergency situations. A label stating that standard pre-transfusion testing has not been performed is attached to the blood bag. Less commonly, they may be due to antibodies against RhD, Duffy, Kidd and Kell antigens. The antibodies (IgM, IgG1 and IgG3) fix complement and this causes intravascular haemolysis. It is most often related to IgA deficiency in the recipient associated with complement-fixing anti-IgA. Group and screen It is of critical importance that blood samples for compatibility testing are correctly identified. This is done either in the hospital blood bank or at the regional transfusion centre. Once an alloantibody is identified, appropriate red cell units, lacking the red cell antigen, are selected. Delayed life-threatening reactions Bacterial contamination this is rare but is usually fatal if red cells are contaminated. Platelets can sometimes be contaminated with bacteria, most often Gram-positive organisms such as Staphylococcus epidermidis. If the cross-match is negative, then a compatibility label, giving patient details, is attached to the unit and the blood and a compatibility report issued. Emergency situations If the situation is life-threatening then group O blood is issued. If the patient is a premenopausal female, Chapter 12: Haematology and immunology 253 may be overlooked as a cause of this clinical picture. Clinical features include fever and a fall in haemoglobin level associated with jaundice between 4 and 14 days after transfusion. Diagnosis requires a positive direct antiglobulin test and the demonstration of an alloantibody either in the serum or in a red cell eluate, which is antibody eluted from the red blood cells. These may be acquired following pregnancy or after transfusion of cellular blood components. Leucodepletion of blood components may be indicated if reactions persist despite this measure. Urticarial reactions Urticarial reactions to donor plasma proteins may be treated with antihistamines. If there are repeated reactions unresponsive to antihistamines, washed red cells should be given. Delayed haemolytic transfusion reactions these reactions occur in patients who have been previously sensitised by transfusion or pregnancy. Red cell antibody titres in such patients may fall to undetectable levels over time, and subsequent re-exposure to the corresponding antigen in a later transfusion can result in a secondary immune response and haemolysis of the transfused cells. IgG antibodies are generally responsible, and haemolysis is generally extravascular, though occasionally it can be intravascular. Emergency treatment of haemophilia and von Willebrand disease when specific concentrates are not available and on the advice of a haematologist Dysfibrinogenaemia associated with bleeding Massive transfusion if the fibrinogen level is < 1. Haemostasis the arrest of bleeding following an injury is a rapid and complex process that involves changes in the involved vessel (smooth muscle constricts and the endothelium becomes procoagulant), platelets (become activated and aggregate) and plasma (fibrin formation). Simultaneous inhibitory mechanisms ensure these processes are confined to the site of injury. Subsequently, the removal of the clot (fibrinolysis) occurs as part of tissue remodelling. Although there are newer theories of the mechanism of clot formation, the classical division into intrinsic and extrinsic systems still has validity and aids understanding. Abnormal coagulation tests are among the commonest reasons for seeking haematological advice. In many cases, the underlying coagulation abnormality and its treatment can be deduced from a basic knowledge of the coagulation mechanism. The classical theory of blood coagulation describing intrinsic and extrinsic systems is useful for understanding in vitro coagulation tests. Such cascade reactions allow for considerable amplification as well as many opportunities for control of the process. Extrinsic pathway the extrinsic pathway is so called because to activate coagulation via this pathway a substance. Tissue factor is a ubiquitous lipoprotein found in particularly high concentrations in placenta, brain and lung. It is also found in monocytes and endothelial cells but is only expressed when these cells are activated. The plasma is preincubated with kaolin and phospholipid to activate the contact factors, calcium chloride is then added, and the time for a clot to form is recorded. Conceptually it is the simplest of all the coagulation tests as it consists of simply adding a solution of thrombin to platelet-poor plasma and measuring the time taken for a clot to form; the addition of calcium is not necessary. The final common pathway sees the conversion of prothrombin to thrombin by factor Xa, with factor Va as a cofactor. Thrombin is central in coagulation, with multiple roles: r It cleaves fibrinogen to form fibrin monomers. Hence the function of the final common pathway can be monitored by using both tests. In reality, since isolated deficiency of factors X or V is rare, the commonest reason for prolongation of both tests in a patient not receiving oral anticoagulants is hypofibrinogenaemia. Thus an alternative view of in vivo coagulation is required in order to Chapter 12: Haematology and immunology 257 then occurs via two highly efficient reactions, resulting in thrombin formation. These are large molecules that act as cofactors in their respective reactions and localise reactions to surfaces. The overall result is an increase by many thousand-fold in the efficiency of the coagulation mechanism. Heparin binds to antithrombin and induces a 2300-fold increase in thrombin inactivation. Reduction in plasma antithrombin levels results in a tendency to venous thrombosis. Thrombin behaves as an anticoagulant when it binds to thrombomodulin, which is present on the endothelial surface. Thus thrombosis is prevented from propagating along normal vessels close to a point of injury.