Irene A. Weiss, MD

• Department of Medicine
• Division of Endocrinology
• New York Medical College
• Westchester Medical Center
• Valhalla, NY

The diaphragm therefore becomes splinted and the lungs compressed hiv aids infection rates for southern africa buy discount aciclovir 200mg, widening the carina and moving it to a higher position in the chest how long after hiv infection do symptoms show buy generic aciclovir 800mg line. A properly placed tracheal tube may enter a main bronchus once the abdomen is inflated hiv infection blood count cheap aciclovir 400 mg without prescription. Blood loss in prostatectomy is related to resection time rather than size of the prostate best antivirus software buy 400mg aciclovir amex, and is generally accepted to be less if spinal anaesthesia is used rather than general anaesthesia hiv infection in new zealand discount aciclovir 200mg on-line. This also has the advantage that any catheter manipulations or bladder washouts necessary in the immediate postoperative period will be covered by the residual effects of the anaesthetic antiviral zona zoster order aciclovir cheap online. Spinal anaesthesia has advantages in those with pre-existing respiratory disease, though its use in the presence of ischaemic heart disease is more contentious. Blankets covering the upper body may also help, but the majority of re-warming must be done in the postoperative period. Blood loss at prostatectomy can be difficult to assess, though a variety of methods are available. This is a major undertaking and is not the same operation as a retropubic prostatectomy. Airway maintenance is usually with a tracheal tube, and invasive monitoring is common. This solution is deliberately non-electrolytic so that the diathermy current is applied to the tissue rather than being dissipated in the fluid. If significant volumes of this solution get into either the general circulation or the tissues, from where it is absorbed, then there may be serious fluid and electrolyte disturbances. Cerebral oedema develops, leading to confusion, hypertension and bradycardia, though loss of consciousness or convulsions is not uncommon. Respiratory distress accompanied by hypoxia (because of interstitial pulmonary oedema) and cardiac effects such as rhythm and contractility changes may also be seen. It has an intravascular half-life of 85 minutes, and breakdown products include oxalate and ammonia. The plasma sodium concentration may fall to extreme levels: below 100 mmol l-1 is not unknown. If the irrigation fluid is in the tissues or free in the peritoneal cavity then laparotomy for drainage may be the only possible method of treatment. Emergency anaesthesia in this situation is fraught with difficulties, but it is one of those occasions when the patient must be accepted as they are, without any attempt to improve the situation in the preoperative period. General anaesthesia employing intubation and controlled ventilation is the first choice. The use of breath alcohol estimations can give an estimate of fluid absorption during the procedure, and this technique is gaining popularity for resectoscopic surgery. Anaesthesia for this would normally involve general anaesthesia with tracheal intubation, epidural analgesia and invasive monitoring, followed by admission to an intensive care bed. Continuous epidural analgesia is particularly effective for both types of incision. Pyeloplasty is usually carried out in the lateral position through a loin incision and the above comments apply. Occasionally patients will be anaemic at presentation from frank blood loss over a period of time. Use of diathermy in the bladder can stimulate the obturator nerve, which is close by in the pelvis, lateral to the bladder. This situation can only be prevented by using muscular relaxation and controlled ventilation. Good relaxation is also necessary for adequate bimanual surgical assessment of the tumour and the bladder, and anaesthesia should not be terminated until this is complete. As time passes new medical conditions may appear or pre-existing conditions deteriorate, so a full preoperative assessment should be carried out at each admission. A large needle is passed under x ray control into the relevant renal calyx and a largebore cannula passed along the track. The endoscope is then passed through this cannula accompanied by continuous irrigation with glycine or saline, depending upon the method used to extract the stones. Saline is used with electrohydraulic lithotripsy whereas glycine or saline may be used with the lithoclast. There can be considerable blood loss and significant absorption of irrigating solution causing facial and cerebral oedema. Standard anaesthetic techniques for this involve tracheal intubation, controlled ventilation and epidural analgesia for postoperative pain relief. The epidural dressing must be waterproof and be placed away from the operative puncture site. The usual precautions are necessary for the prone position, particularly eye protection and padding of pressure points. Care should be exercised in the tension of any bandage used to tie in the tracheal tube, as the facial oedema may cause this to cut into the patient, increasing the possibility of a restricted cerebral vascular supply. This procedure can be a major physiological strain on patients with ischaemic heart disease. The patients should be admitted to a high dependency unit for the immediate postoperative period, though the less healthy patients may require the full facilities of an intensive care unit on a planned basis. Nephrectomy Nephrectomy for benign disease is usually carried out through a loin incision, whereas if malignancy is involved (including ureteric disease) the operation is generally performed through a laparotomy. The essential difference is the position of the patient, supine for laparotomy but in the lateral position for the loin approach. When in the lateral position the operating table may be arched to increase the distance between the rib cage and the pelvis to improve surgical access. In both positions there may be significant blood loss because of damage to renal vessels close to the aorta or inferior vena cava. In left-sided operations the diaphragm and pleura are in danger, and the anaesthetist should be prepared to deal with pneumothorax. The vessels of the dependent arm may be partly occluded in this position, and therefore all monitoring and infusions should be on the upper arm. Some practitioners are using propofol and remifentanil infusion techniques, awakening the patient when required. Obviously this requires acceptable analgesia, for which local anaesthetic infiltration is used. Orthopaedic surgery Joint replacement surgery the most frequently performed operations in this category are hip and knee arthroplasty. Total hip replacement may be carried out under epidural, spinal or general anaesthesia. Hip replacement may be carried out in the supine or lateral positions, and it is essential, especially in this relatively older patient group, that great care is taken in positioning the patient and protecting any potential pressure areas (see Section 1, Chapter 3 for other positioning guidance). Revision surgery and bone grafting to the acetabulum complicate the procedure greatly and add to the likelihood of extensive blood loss and the need for close haemodynamic monitoring. The most major incident to anticipate is cement reaction, which generally occurs with cementing of the femoral, rather than the actetabular, prosthesis. It is important that fluid balance is adequate before the cementing of the femoral component. Although less common, a similar reaction may be seen after cemented humeral prostheses. Anaesthesia for total knee arthroplasty is broadly similar but does not show the same picture of cement reaction unless extra-long femoral components are used after extensive reaming. Femoral and sciatic blockade may be used for analgesia or operation, and in general techniques of anaesthesia are as for hip arthroplasty. The use of a tourniquet restricts blood loss intraoperatively, but postoperative losses may be brisk. After release of the tourniquet metabolic products are released into the circulation, representing an acid load which may cause temporary acidosis and a rise in end-tidal carbon dioxide. Bilateral joint replacements are severe surgical insults that should not be undertaken lightly. Adequate eye care is important, and there is no substitute for endotracheal intubation (possibly with an armoured tube) and controlled ventilation using individual drugs of choice. A suitable support should be employed to avoid abdominal compression, which will both embarrass ventilation and cause venous congestion in the epidural plexus. Fractured neck of femur There are several operations for the treatment of fractured neck of femur (dynamic hip screw, cannulated screws, etc. The majority of patients presenting for this procedure are elderly and frail, and may be the victims of severe polypharmacy. As the operation is urgent rather than emergency, attention should be paid to the correction of those features that can be improved (uncontrolled atrial fibrillation and electrolyte imbalance, to name but two). Epidural and general anaesthesia may also be used, and although the mortality from general anaesthesia is higher in the short term, there is very little difference after three months or so have elapsed, when death rates from all techniques approximate. The use of irrigating solutions containing 1% alcohol is recommended, as absorption can be monitored by the measurement of breath alcohol using a suitable meter and normogram tables. General anaesthesia with spontaneous ventilation via a face mask or laryngeal mask is therefore adequate. Laparoscopy Laparoscopy involves the inflation of the abdomen with carbon dioxide before the insertion of an endoscope to examine the abdominal contents. Although the procedure is possible with the patient breathing spontaneously, this is not recommended and controlled ventilation with muscular relaxation is the norm (suitable agents being mivacurium and atracurium). The procedure is usually of short duration and not accompanied by great postoperative discomfort except in the case of sterilisation or other tubal surgery, where the presence of occluding clips on the Fallopian tubes may precipitate spasm. The most alarming problem during laparoscopy is that of a severe bradycardia which may be precipitated on inflating the abdomen. Vagolytic drugs should be always at hand, and if necessary the abdomen should be deflated until the heart rate stabilises. The patient must be carefully assessed to ensure that there is no great degree of concealed blood loss. The onset of muscle relaxation under anaesthesia in a patient with a bleeding ectopic pregnancy can result in sudden, massive haemorrhage, in which case aggressive fluid replacement and urgent laparotomy are required. Large-scale blood replacement should always be followed by haematological assessment of coagulation and appropriate remedial therapy. Gynaecological surgery Hysterectomy Hysterectomy may be undertaken by abdominal or vaginal route. Abdominal hysterectomy equates to a laparotomy in its anaesthesia requirements, although the use of a low transverse incision has encouraged the use of the laryngeal mask airway instead of endotracheal intubation (assuming no other contraindications, such as morbid obesity). Muscular relaxation and controlled ventilation are usually required, with volatile agent and opioid of choice. Vaginal hysterectomy is less of an insult than abdominal hysterectomy but has broadly similar anaesthesia requirements. Caudal injection of local anaesthetic agents provides a degree of postoperative analgesia, although it is unlikely that the level of block from this technique will reach sufficient height to be fully effective (T10); therefore, additional analgesia should be provided. If rectal drug administration after pelvic floor repair is desired, this is best administered by the operating surgeon after completion, when the suppository can be gently inserted without damage to the suture line. As the volatile anaesthetic agents have a relaxant effect on the uterus, their use is associated with increased blood loss, although this may not reach clinical significance. Propofol with or without supplemental opioid agent is popular for what is a short, minimally disruptive procedure. Ear, nose and throat surgery Laryngoscopy Direct laryngoscopy and its variants (which may include the use of lasers in the airway) demand special techniques of airway management because the surgeon works directly in the airway and needs access to the larynx. Specially designed small tracheal tubes, tubes with a cuff and an insufflation port or special laser-proof tubes are available, and all have their uses. Because of the difficulties of maintaining spontaneous or controlled ventilation under these circumstances, the usual techniques involve a total intravenous technique with controlled ventilation using an insufflation device such as the Sanders injector or highfrequency jet ventilator. If lasers are to be used in the airway then great care must be taken to isolate the trachea below the tube cuff from the airway above the cuff, because any backwash of gas containing oxygen might result in an explosion or fire when the laser is next fired. 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 a wise counsel. 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 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 beta-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 anti-emetic agent should be administered during the procedure, as nausea from disturbance of labyrinthine function is frequent and postoperative vomiting is particularly undesirable. Tonsillectomy Anaesthesia for tonsillectomy with or without adenoidectomy requires defence of the shared airway from blood and debris.

Valves within lymph vessels maintain unidirectional flow towards the thoracic ducts hiv infection nhs aciclovir 800mg low cost, which drain into venous blood at the junction of internal jugular and subclavian veins hiv kidney infection order cheap aciclovir line. External compression from adjacent pulsatile arteries and skeletal muscle contractions augment lymph flow through larger lymphatic vessels hiv infection and aids are you at risk buy aciclovir 200mg overnight delivery. Capillary filtration equilibrium In a capillary there is normally a dynamic equilibrium between the fluid filtered out hiv infection real stories buy genuine aciclovir on-line, the fluid reabsorbed and the fluid absorbed by lymphatics hiv infection rates ukraine cheap aciclovir online mastercard. The protein concentration is two to three times higher in lymph draining from liver and intestine hiv infection of macrophages buy aciclovir on line. The accumulation of abnormal amounts of interstitial fluid results in tissue swelling and is referred to as oedema. This is achieved by simultaneous regulation of the cardiac pump and the peripheral vascular system. Control of the peripheral vascular system regulates the relative intravascular volume that influences venous return to the pump, varies vascular resistance to maintain perfusion pressures, and distributes appropriate flows to the various vascular beds. Most areas of the peripheral vascular system are under both local and systemic control, but may be dominated by one set of mechanisms more than the other. Circulation in the heart and brain are mainly regulated intrinsically to maintain perfusion independently of systemic disturbances. On the other hand perfusion of the skin and gut are largely controlled extrinsically, increasing the flexibility to maintain vital organ perfusion under adverse conditions. Contractions are relatively slow, develop high forces and are maintained for longer durations when compared with striated muscle fibres. Contraction occurs in response to systemic and locally released agents such as catecholamines, acetylcholine and prostaglandins. The majority of vascular smooth muscle is innervated by sympathetic fibres that maintain a basal level of vascular tone. The parasympathetic system supplies a small fraction of visceral vessels, which can produce a decrease in vascular resistance when stimulated. Local mechanisms controlling blood flow Autoregulation the blood flow to certain organs. This process is known as autoregulation, and it is achieved by various mechanisms. These mechanisms include mechanical responses of smooth muscle, the accumulation of metabolites or products of injury, and the release of factors by the endothelium. Increasing or decreasing the tone of the smooth muscle in arterioles (vasoconstriction or vasodilatation) varies the perfusion pressure across a vascular bed. Changes in these vessels also affect flow rates through the capillaries and alter vascular resistance. Increasing or decreasing the tone of smooth muscle in the venous system (venoconstriction or venodilatation) varies the relative intravascular volume since the venous system contains >60% of the blood volume. Metabolic regulation this is the most important control mechanism since it determines the balance of oxygen supply and demand for individual tissues and organs. Exposure of tissue to hypoxia or injury results in the release of factors or accumulation of metabolites, which increase capillary permeability and blood flow. Some examples are: r Tissue hypoxia or the accumulation of carbon dioxide and hydrogen ions by diffusion around an arteriole causes vasodilatation. Lactic acid, and to a lesser extent pyruvic acid, produced in anaerobic metabolism, vasodilate by reducing tissue pH. Adenosine dilates hepatic arteries in response to a fall in flow in the hepatic portal vein. Arterioles Resistance vessels, or arterioles, possess a high proportion of smooth muscle in their walls. The smooth muscle fibres are arranged circumferentially in the media, and the effect of varying the muscle tone can range from complete obliteration of the vessel lumen to maximal dilatation. Vascular smooth muscle Vascular smooth muscle differs from both skeletal muscle and cardiac muscle, both structurally and functionally. There is an initial red reaction due to arteriolar dilatation caused by the mechanical stimulus. An axon reflex causes a rapid, more widespread brighter red reaction due to further vasodilatation. Mechanical responses of smooth muscle Myogenic mechanism Vascular smooth muscle contracts or relaxes in response to changes in transmural pressure. When perfusion pressure in a vessel varies, although blood flow may change initially, the vessel subsequently constricts or dilates in response to the altered transmural pressure, maintaining constant blood flow. Isolated muscle preparations suggest that this local response can maintain constant blood flow over perfusion pressures from 20 to 120 mmHg. Endothelial mechanism When flow through a vessel is varied without changes in transmural pressure, increases in flow velocity are associated with dilatation of the vessel. Its role is uncertain but it may act locally to maintain perfusion in different parts of the circulation. The endothelins have multiple physiological effects although their exact role remains uncertain. These effects include contraction of vascular smooth muscle, positive inotropy and chronotropy, reduction of glomerular filtration rate, bronchoconstriction and stimulation of cell growth. Systemic humoral control of blood flow Humoral factors affecting the vascular system include both vasodilators and vasoconstrictors. Catecholamines Under physiological conditions the most powerful humoral agents affecting the systemic vessels are the catecholamines. Epinephrine is released from the adrenal medulla and exerts its primary effect on cardiac muscle. It also dilates resistance vessels in skeletal muscle via adrenergic fibres at low concentrations. At higher concentrations -adrenergic effects predominate, causing vasoconstriction. Norepinephrine is a powerful vasoconstrictor and is controlled mainly via its release from sympathetic nerve endings as opposed to its release from the adrenal medulla. Prostacyclin is a vasodilator and inhibits platelet aggregation, while thromboxane A2 is a vasoconstrictor that promotes platelet aggregation. Regular administration of aspirin causes a predominance of prostacyclin effects, providing prophylaxis against myocardial infarction and stroke. In supranormal doses vasopressin increases blood pressure by systemic vasoconstriction. Angiotensin the juxtaglomerular apparatus of the kidney synthesises and stores renin. Aldosterone increases tubular reabsorption of sodium and, by osmotic effects, water, and stimulates the excretion of potassium and hydrogen ions. Hypersensitivity reactions can result in a massive release of histamine, with a disastrous drop in blood pressure due to generalised vasodilatation. In association with sensory neurones, substance P causes vasodilatation and increases capillary permeability. The rate of release from atrial muscle cells is proportional to the stretch of the atria obtained by changes in central venous pressure. Systemic neurological control of blood flow All blood vessels except capillaries and venules possess smooth muscle in their walls and are supplied by sympathetic motor fibres. The fibres supplying blood vessels form a plexus in the adventitia, and then extend to the outer layers of smooth muscle cells in the media. These sympathetic fibres possess a normal resting firing rate or tone, which may be increased or decreased. The vascular smooth muscle is innervated by noradrenergic sympathetic fibres, in which increased activity produces vasoconstriction. However, blood vessels in skeletal muscle are also supplied by cholinergic sympathetic fibres, which cause vasodilatation when stimulated. Constriction of arterioles (vasoconstriction) increases systemic vascular resistance, whereas constriction of veins (venoconstriction), especially splanchnic veins, increases the relative intravascular volume, and hence venous return to the heart. Systemic vascular Kinins Kinins are peptides originating from the exocrine glands. Bradykinin (9 amino acids) and lysylbradykinin (10 amino acids) are recognised vasodilators. The kinins are formed by kallikreins from protein precursors, and are metabolised by kininases. Autonomic reflexes mediate neurological control of the peripheral vascular system. There the sensory information is used to modulate sympathetic tone, which is relayed back to the peripheral vessels via efferent pathways. The pressor region is located rostrally in the ventrolateral medulla, and provides a tonic output that maintains a background level of vascular smooth muscle tone. When the pressor centre is stimulated it causes increased vasoconstriction, increased heart rate and increased myocardial contractility. When stimulated, the depressor region decreases blood pressure by inhibiting the pressor area and also inhibiting sympathetic outflow directly at spinal level. Sympathetic tone is, thus, set by the balance between these two centres, which not only respond to afferents from peripheral reflexes, but are also influenced by central chemoreceptors and higher centres in the brain. There is continuous tonic activity in sympathetic noradrenergic but not cholinergic neurones. The hypothalamus also controls cutaneous vasodilatation and vasoconstriction in response to environmental or body temperature changes. Cardiac baroreceptors, aortic arch baroreceptors and aortic body chemoreceptors relay afferent impulses centrally in fibres (cardiac depressor nerves) of the right and left vagus nerves. They respond to the degree of stretch in the vessel or heart wall, and hence to the pressure (or more strictly the transmural pressure) in the vessel or heart. When intraluminal pressure increases, wall stretch increases and the frequency of impulses discharged by baroreceptors increases. The baroreceptor impulses exert an inhibitory influence on the pressor centre, and baroreceptor control thus represents a negative feedback control system to maintain cardiovascular stability. Baroreceptors respond not only to pressure magnitude but also to rate of change of pressure. At low pressures there are few discharges during the upstroke of arterial pressure. At higher mean arterial pressures, discharges are present throughout more of the cycle. The effect of this is that baroreceptors respond not only to changes in pressure but also to changes in pulse pressure and heart rate. During chronic hypertension, the baroreceptors adapt to higher pressures and the response curve is shifted to the right. Carotid sinus baroreceptors are more sensitive to blood pressure changes than aortic baroreceptors. The carotid baroreceptors also respond to external mechanical stimulation, which increases their firing rate, eliciting an inhibitory vasomotor response. In susceptible individuals this may reduce blood pressure sufficiently to induce syncope. Therapeutically, carotid sinus massage can sometimes be effective in slowing a supraventricular tachycardia. Cardiopulmonary baroreceptor reflex Stretch receptors exist in the atria, ventricles and pulmonary vessels. These receptors protect against rapid changes in intravascular volume by varying their tonic discharge, which exerts an inhibitory influence over the medullary pressor centre. Type A receptors discharge predominantly during atrial systole, while type B discharge during atrial filling, particularly over the later part of diastole. When intravascular volume expands atrial filling is increased, and both A and B receptors are stimulated. The impulses from these receptors are relayed to the medulla by the vagus nerves, which causes inhibition of the pressor centre and stimulation of the sinus node. This results in vasodilatation, a fall in blood pressure, increased renal blood flow, increased urine output, and a rise in heart rate. Carotid and aortic baroreceptor reflex Baroreceptors in the carotid sinus and the arch of the aorta monitor arterial pressure, arterial pulse pressure and heart rate. Bainbridge described the reflex increase in heart rate in response to a rapid intravascular infusion of fluid in anaesthetised animals. The afferent limb of the reflex is the vagus nerves, while the efferent limb consists of sympathetic nerves to the sinus node. Heart rate is thus influenced by the two opposing actions of the arterial baroreceptor reflex and the Bainbridge reflex. Whether the heart rate increases or decreases with a sudden increase in intravascular volume is thought to be dependent on the initial heart rate: if it is high it tends to decrease (arterial baroreceptor reflex), while if the initial heart rate is low it tends to increase (Bainbridge reflex). Thus, inflation of the lungs results in systemic vasodilatation and a decrease in blood pressure. Chemoreceptor reflexes these reflexes are mediated centrally by receptors in the medulla, and peripherally by the carotid and aortic bodies. The chemoreceptors can respond to parameters that reflect hypoxia, hypercapnia, acidaemia or ischaemia. Chemoreceptor reflexes are mainly directed towards respiratory control but do exert some effects over cardiovascular parameters.

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This only occurs in the presence of non-depolarising blockade antiviral film purchase aciclovir 800 mg mastercard, and is probably the result of stimulation of presynaptic acetylcholine receptors that enhance the subsequent release of acetylcholine from the nerve terminal hiv infection flu buy aciclovir 400 mg cheap. However xl 3 vr antiviral buy aciclovir 800mg mastercard, any agonist of nicotinic acetylcholine receptors can also cause blockade if not rapidly cleared from the neuromuscular junction hiv infection diagnosis and treatment discount aciclovir 200mg amex. Measurement of response Assessment of neuromuscular blockade can be made by the observed or palpated strength of twitch how hiv infection spread purchase aciclovir online now, measuring evoked tension in a certain muscle antiviral for chickenpox purchase aciclovir 800 mg otc. Mechanism of action A depolarising block occurs when the agent stimulates the acetylcholine receptor and causes depolarisation. Persistence of the agonist at the receptor prevents repolarisation of the endplate and so it is refractory to further stimulation. As the agent diffuses away from the junctional cleft, repolarisation occurs and muscle action potentials are once more possible. The block may be enhanced by a local increase in acetylcholine, as produced by anticholinesterases. This is followed by a prolonged refractory period, which constitutes the blockade. Neuromuscular test stimulation results in: r Reduced single-twitch height r Reduced train of four, all of equal amplitude r No tetanic fade r No post-tetanic facilitation After suxamethonium administration there may be widespread muscular pains, which are worse on movement. Pretreatment with benzodiazepines, lidocaine or small doses of non-depolarising agents may help. It is synthesised in the liver and is present in the liver, kidneys, pancreas, brain and plasma but not erythrocytes. A reduction in cholinesterase activity may be due either to a deficiency of cholinesterase molecules or to an abnormality of the enzyme. Levels fall to 75% of normal during pregnancy and to 67% of normal during the first 7 days post partum. Plasma cholinesterase synthesis is controlled by a pair of autosomal recessive genes. Assessment of plasma cholinesterase activity includes global plasma cholinesterase activity levels, and dibucaine and fluoride numbers. Plasma cholinesterase may also exist in excess, as a genetic variant or particularly in the presence of obesity or alcoholism. Plasma cholinesterase is also responsible for the metabolism of mivacurium, and the concomitant use of these drugs in susceptible patients may exaggerate problems. Clinical features the predominant effect of neuromuscular blocking agents is a reversible paralysis of skeletal muscle. This reduction in skeletal muscle activity reduces venous return and therefore reduces cardiac output and blood pressure. This is probably a dynamic process, with both acetylcholine and the blocking agent in equilibrium with the receptors. The block can be antagonised by a local increase in acetylcholine, as produced by anticholinesterases. Aminosteroids the acetylcholine-type fragment associated with the D ring of the steroid nucleus is probably responsible for most of the neuromuscular antagonism. The acetylcholine-type fragment associated with the A ring is probably responsible for the cardiovascular effects, especially the vagolytic aspects. In general, the aminosteroids are more slowly metabolised than the benzylisoquinoliniums. Benzylisoquinolinium compounds the chemical structure of benzylisoquinolinium is associated with histamine release. When the alpha site on each of the two subunits is occupied, the channel opens and allows depolarisation. Rapid metabolism enables rapid dissociation of receptor and agonist and the channel closes. Sequence 2: Depolarising blockade Depolarising agent Suxamethonium and the released acetylcholine are both agonists of the receptor. When both receptors are occupied by any combination of these molecules the channel opens. However, the persistence of suxamethonium causes the channel to remain open long after the acetylcholine has been destroyed, maintaining a depolarised refractory endplate. Sequence 3: Non-depolarising blockade Non-depolarising agent Non-depolarising drugs are antagonists and bind to the receptor without opening the channel. They subsequently prevent acetylcholine from binding and as two acetyl choline molecules are required for depolarisation only one receptor needs to be occupied by the antagonist to be effective. Other pathways exist, including spontaneous degradation and enzymatic hydrolysis within the plasma. Anticholinesterases Mechanism of action the anticholinesterases inhibit the breakdown of acetylcholine by binding to the acetylcholinesterase enzyme in a competitive manner. This raises the background concentration of acetylcholine near the neuromuscular junction, which in turn overcomes the reduced number of functional nicotinic receptors on the muscle endplate, whether due to a reduced number of receptors (myasthenia gravis) or due to blockade of existing receptors (non-depolarising muscle relaxants). The anticholinesterases can be classified as either reversible anticholinesterases or organophosphorus compounds. While they all act on acetyl and plasma cholinesterase, the specific interaction with the enzyme varies between individual drugs. Physiologically, the positively charged quaternary amine of acetylcholine binds to the anionic site. The acetyl ester combines with the esteratic site and the acetylcholine is hydrolysed. The anticholinesterases competitively occupy these sites and prevent acetylcholine access. The anticholinesterases have a quaternary amine group that is attracted to the anionic site and a carbamyl ester that binds covalently to the serine amino acid of the esteratic site. The quaternary amine group is not essential for activity, but when present it conveys enhanced potency and stability. When neostigmine is used orally for the treatment of myasthenia gravis larger doses are, therefore, necessary. Physostigmine (no longer available) is an example of an anticholinesterase with several tertiary amine groups rather than the quaternary amine of the others. Edrophonium is only clinically effective for 5 minutes, and is used in the diagnosis of myasthenia gravis. Neostigmine is the only anticholinesterase routinely used to reverse planned neuromuscular blockade in clinical practice. Anticholinesterases have widespread effects subsequent to the stimulation of increased cholinergic muscarinic and nicotinic activity. Excess acetylcholine causes bronchoconstriction and increased bronchial secretion. These problems are prevented by the concomitant use of muscarinic anticholinergic drugs such as atropine or glycopyrrolate. Anticholinesterases can also cause a depolarising neuromuscular blockade when used in excess, or in the absence of non-depolarising blockade. Neuromuscular blockade is terminated either by endogenous elimination of the drug and diffusion of the blocking agent away from the neuromuscular junction, or, in the case of non-depolarising agents, the effects can be overcome, in part, by inhibiting the metabolism of acetylcholine. If a long-acting muscle relaxant is used, it is possible for the blockade to re-establish if the effects of the anticholinesterase wear off before the neuromuscular blocking agent has left the receptors. Cyclodextrins are highly water-soluble, and sugammadex is excreted rapidly in the urine. The half-life is relatively short and so further administration of rocuronium soon afterwards may be an option. An alternative benzylisoquinolinium non-depolariser could also be used, as these larger molecules will not fit within the cyclodextrin cavity. In contrast with anticholinesterase reversal, sugammadex: r Is effective regardless of the state of neuromuscular blockade. In general, they have no ionic binding component but bind covalently and irreversibly to the esteratic site of the cholinesterase enzyme by the release of a relatively weakly bound component of the drug. It is the only organophosphate in clinical use, and is used in the treatment of glaucoma. It too binds covalently to the esteratic site of the enzyme but also has a positively charged quaternary ammonium group that helps binding. Although it is slowly hydrolysed it may nonetheless prolong the action of suxamethonium and mivacurium. In effect, it forms a tube into which a single relatively small steroid molecule of rocuronium fits. Hofmann elimination is the spontaneous fragmentation of atracurium at the bond between the quaternary nitrogen and the central chain. Atracurium is also metabolised by ester hydrolysis, producing a quaternary alcohol and a quaternary acid. Block prolonged by reduced or atypical plasma cholinesterase as with suxamethonium. Block also prolonged if factors interfering with plasma cholinesterase are present. Heterozygotes for atypical plasma cholinesterase show a prolongation of effect of about 10 min Cis-atracurium dibesylate Atracurium contains a mixture of ten geometric isomers. Of it, 40% is deacetylated in the liver to 3-hydroxy, 17-hydroxy and 3,17-dihydroxy derivatives which are eliminated in the bile. The 3hydroxy compound has some neuromuscular antagonist activity Note that pancuronium has some prejunctional activity. Reconstitution with water for injections produces clear, colourless solution of pH 4. Hepatic failure may prolong clinical effect, whereas chronic phenytoin therapy reduces the efficacy of vecuronium. These have minimal neuromuscular and vagolytic activity; only 3-hydroxy is found in any significant quantity and it has 50% of the neuromuscular blocking potency of vecuronium. Its effect is terminated by diffusion away from the neuromuscular junction followed by rapid redistribution and hydrolysis. Neostigmine inhibits the hydrolysis of suxamethonium and mivacurium and other drugs metabolised by plasma cholinesterase. It is effective within 30 s and lasts for several minutes Pharmacokinetics t1/2 3. Sugammadex, a new reversal agent for neuromuscular block induced by rocuronium in the anaesthetized Rhesus monkey. They also stabilise other electrically excitable membranes, and some examples, such as lidocaine, have clinically useful antiarrhythmic activity. Small changes in pH have marked effects on the proportion of drug that is ionised, and therefore markedly influence the effect. Structure Local anaesthetic agents comprise a hydrophilic tertiary amine group linked to a lipophilic aromatic group. Protonation of the highlighted amine nitrogen atom confers activity on the molecule once it is inside the cell. This is important, as only the non-ionised drug passes through the membrane, yet it is only the ionised drug that Mechanism of action Injectable local anaesthetics must be soluble and stable in water. These drugs exist within ampoules in acid solution with a high degree of ionisation, which maintains solubility. Local anaesthetic agents act by blocking the fast sodium channel in neuronal membranes. To do so the drug must be in the protonated form and the ion channel must be in the open state. The drug enters the ion channel from the intracellular direction, but is administered extracellularly.

One of the main purposes of this type of trial is to ascertain what the maximum safe dose of the study drug is and how it is metabolised hiv infection rate dc purchase line aciclovir. They are also called post-marketing surveillance studies and need not contain a control group how long after hiv infection do symptoms occur aciclovir 200 mg without prescription. Crossover studies Crossover studies are the opposite of parallel design studies hiv infection early trusted 400 mg aciclovir, because in the crossover model each participant will receive each of the study interventions hiv infection worldwide buy cheap aciclovir 800 mg on line. The main advantage of this type of controlled study is the ability to determine whether a particular patient does better on a specific treatment antiviral zona zoster aciclovir 800 mg amex. The simplest crossover study design contains two periods during which the subject receives two different treatments antiviral medication side effects order aciclovir cheap. It is crucially important that the interventions are of rapid onset and short duration. If not, then the effect of the treatment in period A may interfere with the effect of the treatment in period B. For example, if a particular disease is cured during period A, then clearly the patient will not enter period B in the same pretreatment state as in period A. It follows that chronic, incurable conditions are better suited to a crossover study. Multi-centre trials the multi-centre trial has gained recent popularity because it increases the power of the study by recruiting larger patient numbers. The multi-centre effort is used when a single centre cannot provide sufficient patients. The cost of a multi-centre trial is invariably higher than that of a singlecentre type, and it takes a lot more organisational effort. Inter-centre differences in patient management may be difficult to eliminate, as variations in working practices in the contributing sites may not be apparent to the investigators immediately and may be difficult to alter. The need to perform a multi-centre trial arises when the variable in question occurs infrequently. For example, a study is set up to compare the incidence of neurological damage after a spinal anaesthetic with two different types of spinal needle. A large number of patients will be required to show whether or not there are any statistically significant differences because the incidence of these complications very low. The main aim of a meta-analysis is to maximise the statistical precision of the effect of a particular intervention. Suppose a researcher wants to review all the published data on the mortality rate of patients in intensive care units who have been treated with drug A. The usual format would be to express all the studies in terms of odds ratios with 95% confidence intervals (see Section 4, Chapter 4, page 881). A meta-analysis combines many studies, some of which may lack statistical significance on their own, to generate a larger sample that may in totality answer the research question. The potential problems of combining individual studies, with vast differences in outcomes and outcome measures, must not be underestimated. Other limitations of meta-analyses result from the potential for bias from various sources. Also, meta-analyses use statistical techniques that are still poorly understood by reviewers and readers. At times, a meta-analysis is wrongly seen as a substitute for a large, well-conducted, randomised controlled trial. Design of a trial As can be seen from the above, there are a variety of study designs available to investigate the efficacy of a medical intervention or treatment. The strength of the evidence depends on the chosen design, and varies from anecdotal evidence to a randomised, controlled, double-blind trial. It is of pivotal importance that a trial starts with a clearly defined question and an outlined means of assessing the outcome, including statistical methods. Issues which should be addressed from the outset when designing a trial will now be considered further. Sample size A power analysis is used to maximise the chance of finding a statistical difference between groups, where a real difference exists. This calculation of the required number of subjects should take place early on in the planning of the trial. The difficulty with this calculation is that it is often based on pilot studies or previous studies with very small numbers. This is often due to the fact that these initial studies are not randomised and have a huge potential for bias. In deriving the required number Meta-analysis A meta-analysis is a statistical combination of a number of independent trials, usually expressed with confidence intervals. The power of a study is the likelihood of the null hypothesis being rejected correctly. Investigators may inadvertently favour particular observations or changes, or they may deliberately introduce bias. Variability Variability in the interpretation of the outcome measures can reduce the chance of finding a statistically significant difference. Such variability may arise from instrument precision, observer variability, or a combination of the two. Both intra-observer and inter-observer variability are wellrecognised sources of error. Ways of reducing variability include the introduction of technology (for example automated rather than manual blood pressure measurement), and repeated and blinded assessments. Repeated assessments take a pooled value for the variable, and this may be a better reflection of the required variable. Randomisation the purpose of randomisation is to ensure that every participant in the study has the same chance of ending up in any of the treatment groups. A logical consequence of this will be that each group will contain subjects with similar characteristics. Allocating patients on the basis of year of birth (odd or even), hospital number, day of admission or by alternating allocation to each group leads to imbalance or bias. Acceptable methods include the use of computer-generated random numbers, flipping a coin or rolling dice. Despite the use of these randomisation methods, groups may become vastly different at some point during the study. There are basically two types of randomisation techniques available to try and minimise these differences: r the number of patients in each group can be kept as close together as possible by the process of block or restricted randomisation. The total number of patients to be studied is divided into blocks of equal numbers. Bias Bias types the main strength of a randomised controlled trial depends heavily on its potential to minimise selection bias. With the correct application of the appropriate techniques, the study groups can be kept as similar as possible from the outset of the study. This will enable the investigators to establish more reliably the true effect of the intervention studied. Block randomisation is used for each variable, thus ensuring equal distribution of these characteristics across all groups. Blinding Bias frequently results from either the patient or the investigator(s) knowing which type of treatment is being administered. To minimise this potential for distortion, the investigator and the patient should be unaware of the type of treatment assigned. In a single-blind trial, the investigators are aware which group the patient is allocated to . A clinical trial should ideally have a double-blind design, in which neither the patient nor the investigator is aware of the treatment identity. Although the term double-blind is frequently used in medical literature, it is likely that many such studies are not completely double-blinded. For example, a drug which is being investigated may have a clear therapeutic or side effect. The investigator and even the patient may recognise these effects, and this is then a source of (ascertainment) bias. Implementation of trial design Ethics committee approval the most important function of a local ethics committee is to protect the potential subjects of medical research. They should also ensure that valuable resources are not wasted on research that is unlikely to answer the proposed question. In the United Kingdom, these committees are set up either at county level, or even at hospital trust level, particularly at teaching trusts. Most ethics committees have lay members on them, to represent the views of the public. Before the recruitment of patients may begin, approval of the local ethics committee should be obtained. A detailed explanation of the proposed study must be enclosed, including a review of previously published papers. The reason for undertaking the study must be explained and potential advantages to medical science or practice demonstrated. A patient information leaflet explaining the purpose of the study and a consent form, which is to be signed by the patient and the investigator, are also necessary before ethics committee approval can be obtained. To minimise the potential for bias, the method of data collection and interpretation should be determined when the study protocol is drawn up. Problems in data collection can occur because of incorrect data, missing data or problems arising as a result of variability. Incorrect or missing data is usually linked to human error or the inability to collect all the necessary information. As discussed before, inter- and intra-observer variability can be responsible for failing to detect a real statistical difference. The data collectors should have adequately detailed knowledge of the study protocol. Secondly, the data collectors should have forms with a brief synopsis of the guidelines on them, to refer to as necessary. Closed questions with yes or no answers or tick-boxes are preferable to open-style essay questions. Thirdly, the people collecting the data should have had sufficient training in the process of data collection. Whenever possible, a test period should precede the start of the clinical trial to highlight any potential pitfalls or flaws in the protocol. Data analysis As with the collection of data, it is crucially important to determine the analysis technique to be used when the protocol is being drawn up. The statistical tests that will be employed should be appropriate for the type of data. Subsequent exclusion of a number of randomised patients from a clinical trial is a problem that is often difficult to prevent. They may develop complications or morbidity that precludes them from further participation in the study. The problem of missing or incomplete data can be particularly difficult to prevent. It is essential that the number of patients excluded from the study be mentioned in the publication, as well as the reason for elimination. Data collection the data to be collected in a clinical trial may come from various sources. The investigators must review their data critically and truthfully, and when submitting material to journals, adhere to the guidelines for manuscripts. The manuscript should provide a detailed account of the methods employed in the trial, so readers can assess the validity of the procedures, including the statistical methods that were used. An author is someone who has been involved in the design, the implementation, the data analysis and the drawing of conclusions from that study. The manuscript should include a comparison with other articles published on the same or similar subject, with references supplied. It may be that the outcome of the trial raises more questions than it has answered. If appropriate, the social and financial implications must be discussed, and whether the patients and circumstances in the trial are in any way comparable and suitable to the general population. When two variables (x and y) are related, changes in one variable produce a change in the other. A mathematical function expresses this relationship as y = f(x) this means that y is a function of x. Relationships between physiological variables are generally non-linear, but some can be approximated to linear functions over limited ranges. Linear functions and proportionality If two variables, x and y, are proportional to each other, fractional changes in x will produce similar changes in the value of y. Thus if x is doubled, y will be doubled, and if x is halved the value of y is also halved. An example of such a relationship exists when a spring is stretched, where x = the stretching force applied to the spring, and y = the extension produced. In this case the graph of y against x is a straight line passing through the origin. If we now consider the effect of the force (x) on the length (y) of the spring, then the graph of y against x is different. It is still a straight line with a gradient = M, but it no longer passes through the origin. The relationship between y and x then becomes: y = Mx + C C is known as the intercept. Other examples of linear functions are: r the variation of voltage with current in an electrical resistor r the increase in length of a metal rod with temperature Non-linear functions When the graph of a function does not take the form of a straight line, the function is said to be non-linear. Often non-linear functions contain multiple terms which are higher powers of x.