Theodore Abraham, MD

• Director, Hypertrophic Cardiomyopathy Clinic
• Associate Professor of Medicine, Johns Hopkins
• University School of Medicine
• Associate Director of the Echocardiography
• Laboratory at Johns Hopkins Hospital
• Baltimore, Maryland

Identify the lateral border of the pectoralis major and palpate the axillary arterial pulse at this level on the medial surface of the arm symptoms food poisoning purchase pirfenex online pills. Fix the artery with the non-dominant index finger and insert a 22 G short-bevel medications for high blood pressure pirfenex 200mg overnight delivery, 3 medications 25 mg 50 mg purchase pirfenex 200mg mastercard. The needle should be immobilised at this stage and the injection made after negative aspiration treatment yeast infection nipples breastfeeding pirfenex 200 mg line. Digital pressure applied distal to the needle during the injection and maintained while the needle is removed and the arm adducted after injection will encourage proximal spread of solution medications during pregnancy chart cheap 200mg pirfenex mastercard. The interscalene groove runs caudally and laterally between the anterior and middle scalenus muscles medications 512 generic pirfenex 200mg with amex, towards the midpoint of the clavicle. Injection is commonly performed at this point under ultrasound guidance, by placing a linear probe across this point aligned parallel to the clavicle. This block may also be performed by landmark technique in the absence of ultrasound facilities. Drugs, doses and volumes knowledge of the regional anatomy is still required in order to interpret the scan. Identification of the interscalene groove is essential in order to perform this block effectively and safely. If the muscular landmarks are difficult to identify, ask the patient to lift his or her head slightly off the pillow to throw the muscle into relief; the interscalene groove can be highlighted by vigorous sniffing. Raise a skin weal of local anaesthetic at this point and then insert a 22 G short-bevel 3. It is not crucial to feel the arterial pulse, if the groove can be identified accurately. The patient may experience parasthesiae in the distribution of the superior trunk (C5/6, median, musculocutaneous or radial nerves). Aspirate to ensure that the needle has not entered the subclavian artery and slowly make the injection. If arterial blood is aspirated, carefully withdraw the needle a few millimetres until aspiration is negative; the needle will still be within the fascial sheath and the injection can be made as normal. Digital pressure proximal to the needle insertion will encourage distal spread as the large volume is injected. Attention should always be paid to maximum doses of local anaesthetic agent when calculated on a body-weight basis. For axillary block the technique will be most effective in the medial aspect of the upper arm, forearm and hand, whereas for supraclavicular block distribution is fairly uniform below the shoulder but may be less dense in the ulnar aspect of the hand. The main indication is for major orthopaedic procedures of the lower limb, especially surgery to the femur and knee joint. Postoperative analgesia following a total knee replacement or cruciate ligament reconstruction can be impressive, as a single-shot femoral nerve block may last up to 24 hours if bupivacaine 0. Position the patient supine and identify the inguinal ligament and the femoral arterial pulse immediately distal to it. Having raised a skin weal of lidocaine, insert a 22 G short-bevel regional block needle at about 45, aiming cephalad. A distinct pop as the needle pierces the fascia lata may be felt, followed by a secondary pop as it enters the nerve sheath. Parasthesiae in the distribution of the femoral or saphenous nerves indicates close proximity to the nerve. In anaesthetised patients, a peripheral nerve stimulator will aid accurate location. Duration can be extended by the insertion of a catheter into the femoral nerve sheath for continuous infusion. The only significant complication of femoral nerve block is the accidental injection of local anaesthetic into the femoral vessels, which are immediately adjacent to the nerve. The sural nerve runs subcutaneously between the lateral malleolus and the calcaneus to supply the lateral border of the foot. Drugs, doses and volumes anaesthetised for many hours, and it must therefore be protected from pressure sores and prolonged immobility. Ankle block Indications the nerve supply to the foot can be blocked at the ankle to provide surgical anaesthesia and postoperative pain relief for any operation performed distal to the malleoli. The main indications are orthopaedic and trauma surgery to the forefoot and digits. Surgery such as correction of hallux valgus is very painful, and ankle blocks, using bupivacaine 0. Although it is usual to perform a combination of blocks at the ankle under general anaesthesia, it is possible to use the technique in conscious patients. Complications the main complications of these nerve blocks are the potential for intravascular injection or vascular trauma, as all the injections are made into neurovascular bundles (except the sural nerve). However, the volumes of local anaesthetic are small, the needle used should be no larger than 23 gauge, and aspirating the needle before each injection will minimise the risk. Many patients will be mobilised soon after surgery, and they must be supervised and non-weight bearing while the blocks are still working because they will have no sensory or proprioceptive awareness in the sole of the foot if the tibial nerve has been blocked. The five nerves which supply the foot and the ankle are the terminal branches of the femoral and sciatic nerves. The saphenous nerve is the terminal branch of the femoral nerve and supplies the skin over the medial malleolus and a variable amount of the medial border of the foot. The other nerves are branches of the sciatic nerve, which divides into the common peroneal and tibial nerves within the popliteal fossa. The deep and superficial peroneal nerves emerge onto the dorsum of the foot at the level of the extensor skin crease between the pulse of the dorsalis pedis and the tendon of extensor hallucis longus. The deep peroneal nerve supplies the deep structures of the dorsum of the foot and the skin of the first webspace only; the superficial peroneal nerve supplies the skin of the dorsum of the foot and the lateral three webspaces. The tibial nerve runs in a sulcus behind the medial malleolus, deep to the medial collateral ligament of the ankle, accompanied by the corresponding tibial Anatomy Abdominal wall blocks Inguinal field block Indications Inguinal field block in combination with light general anaesthesia is ideally suited to day-case repair of a hernia. If the surgery is to be performed using local anaesthesia as a sole technique, a larger volume of more dilute local anaesthetic is preferable, and the surgeon may need to reinforce the anaesthesia by direct infiltration of the deeper structures within the inguinal canal. At the midpoint of a line between these two bony landmarks insert a 23 G needle at 90 to the skin until it just touches the periosteum of the calcaneus just below the sustentaculum tali, which can be felt as a crescent-shaped protuberance on the calcaneus. If the injection is in the correct plane, deep to the medical collateral ligament, the local anaesthetic will spread proximally and distally along the course of the tibial nerve. Deep peroneal nerve Position the foot at right angles to the tibia and palpate the pulse of dorsalis pedis. Identify the tendon of extensor hallucis longus by moving the great toe and insert a 23 G needle between these two landmarks at 45 to the skin until contact is made with the distal end of the tibia. Superficial peroneal nerve Withdraw the needle into the subcutaneous tissue having completed the deep peroneal injection, and realign it, aiming towards the lateral border of the foot. Sural nerve Palpate the lower border of the lateral malleolus and the lateral aspect of the calcaneal tuberosity and make a subcutaneous injection of 5 mL of local anaesthetic between these two points. Make a skin weal of lidocaine at this point and insert a 22 G short-bevel regional block needle, at right angles to the skin, directly downwards through the skin and subcutaneous tissue. Move the needle from side to side in a horizontal plane and a distinct scratching over the surface of the aponeurosis will be felt. The iliohypogastric nerve (T12/L1) lies just deep to the aponeurosis, so once the needle penetrates it, immobilise the needle and inject 5 mL of local anaesthetic. Withdraw the needle to the subcutaneous tissues and infiltrate a subcutaneous, fan-shaped area, using 10 mL of solution to block the terminal fibres of the subcostal nerve (T12). Insert the needle directly down to the tubercle and inject 5 mL of solution around the external inguinal ring to anaesthetise the genitofemoral nerve (L1/2). Make a second fan-shaped subcutaneous infiltration to block any fibres that may cross the midline. The ilioinguinal and iliohypogastric nerves run in the plane between the internal oblique and transversus abdominis muscles. The genitofemoral nerve enters the inguinal canal and runs in the spermatic cord or with the round ligament of the uterus, to exit and become subcutaneous at the pubic tubercle. Anatomy the inguinal area is supplied by the ilioinguinal and iliohypogastric nerves, which are terminal branches of spinal nerve L1. Complications There are few important complications, as the technique is mainly one of infiltration together with the discrete blockade of three small peripheral nerves. From the first point of injection, puncture of the peritoneum and viscera is possible if a long needle is used. Inadvertent intravascular injection is always a possibility with the second point of injection, especially the femoral vessels. It is also possible to block the femoral nerve from the same point, and the patient may complain of pain in the hernia site and a numb, heavy leg. In many patients the identification of the triangle can be challenging, generally due to excessive adipose tissue but also to the anatomical variation in its location on the lateral abdominal wall. An in-plane technique enables the advance of the needle in an anteromedial direction to be made under direct observation, to the plane between internal oblique and transversus abdominis muscles. It provides effective supplementary analgesia after lower abdominal surgery, with a reduction in pain scores and opioid requirements. The point of needle insertion is identified by palpating the triangle of Petit, an area posterior to the mid-axillary line circumscribed by the iliac crest, latissimus dorsi and external oblique muscles. Complications Intraperitoneal penetration and visceral perforation has been reported with the landmark technique. Analgesia is comparable with that produced by a caudal block and avoids the motor and sensory effects on the legs and the autonomic dysfunction of bladder and bowel control. There are no major complications provided that adrenaline or other vasoconstrictors are not used and intravascular injection is avoided. Palpate the inferior edge of the pubic symphysis with the non-dominant index finger and insert a 21 G (adult) or 23 G (paediatric) needle at about 45 until it contacts the pubis or passes just caudad to it. After careful aspiration, make a single injection in the midline (both dorsal nerves may be reliably blocked by a single injection). In an adult, inject 7 mL and then inject a further 3 mL as a subcutaneous weal across the midline of the ventral surface of the penis at its junction with the scrotum, starting approximately 1 cm lateral to the midline raphe and finishing 1 cm lateral on the other side. It is important to keep the needle subcutaneous while making this injection as the urethra is superficial at this point. In children the volume needs to be reduced pro rata according to body weight and penile size. Local anaesthesia of the upper airway Anatomy the shaft and glans of the penis are supplied by a pair of nerves (the dorsal penile nerves) which are terminal branches of the pudendal nerve (S2, 3, 4). The perineal nerves (from the other branch of the pudendal nerve) which innervate the anterior part of the scrotum and the midline ventral surface of the penis need to be blocked for complete penile analgesia. The mucosal surfaces of the mouth, oropharnyx, glottis and larynx may be anaesthetised by a combination of topical anaesthesia and discrete nerve blocks. Indications Intubation of the trachea in patients with difficult airway due to trauma or disease. The trigeminal nerve supplies the nasopharnyx, palate (V2) and anterior aspect of tongue (V3). The glossopharyngeal nerve supplies the oropharnyx, posterior aspect of tongue and soft palate. The superior laryngeal nerve emerges beneath the inferior edge of the greater cornu of the hyoid before it divides into the internal and external branches. Drugs, doses and volumes Avoid local anaesthetic solutions that contain adrenaline. Depress the tongue and spray a further four puffs onto the posterior part of the tongue and pharynx. Although the superior laryngeal nerve can be topically anaesthetised by placing a pledget soaked in lidocaine 2% into each pyriform fossa with Krause forceps, once the mouth and tongue are blocked, it is more usually blocked discretely as follows. Place the patient supine with the head extended and palpate the hyoid bone just cephalad to the thyroid cartilage. To complete the airway anaesthesia, with the patient in the same position as above, palpate the inferior border of the thyroid cartilage and, having first anaesthetised the skin, insert a 21 G, 2.

The attempt must be well run symptoms carbon monoxide poisoning order genuine pirfenex line, under good leadership treatment 4 anti-aging purchase pirfenex discount, and the resuscitation team must be comfortable with the concept of family members being present treatment of hyperkalemia cheap pirfenex online master card. Presence of relatives during resuscitation attempts the concept of relatives being present during resuscitation attempts was first introduced during the 1980s medicine on airplane order 200 mg pirfenex free shipping, mainly in the case of paediatric resuscitation medicine 60 purchase pirfenex 200mg overnight delivery. Subsequent surveys showed that the majority of relatives found the experience of great value symptoms 7dpo 200mg pirfenex otc, and were the circumstances to be repeated they would wish to be present again. They found it gave them a realistic view of resuscitation, and they could see that everything was being done for their child. It also helped them come to terms with the reality of death and eased the bereavement period. A severely injured patient who is hypoxic, in haemorrhagic shock, or who has an expanding intracranial haematoma, for example, will need rapid, effective resuscitation. The aim is to restore cellular oxygenation before the onset of irreversible shock. Physiological responses to haemorrhage Trauma compromises tissue oxygenation because haemorrhage reduces oxygen delivery while at the same time tissue injury and inflammation increase oxygen consumption. Compensatory responses to haemorrhage are categorised into immediate, early and late. The loss of blood volume is detected by low-pressure stretch receptors in the atria and arterial baroreceptors in the aorta and carotid artery. Efferents from the vasomotor centre trigger an increase in catecholamines, which causes arteriolar constriction, venoconstriction and tachycardia. Long-term compensation to haemorrhage is by several mechanisms: reduced glomerular filtration rate, salt and water reabsorption (aldosterone and vasopressin), thirst, and increased erythropoiesis. A decrease in systolic pressure suggests a loss of > 30% Pathophysiology of trauma and hypovolaemia Several mechanisms are involved in the development of cellular injury after severe trauma. The commonest is haemorrhage, causing circulatory failure with poor tissue perfusion and generalised hypoxia (hypovolaemic shock). Myocardial trauma may cause cardiogenic shock, while spinal cord trauma may cause neurogenic shock. Pure haemorrhage without the presence of significant tissue injury may not cause this typical pattern of a stepwise increase in heart rate. Occasionally, the heart rate may remain relatively low until the onset of cardiovascular collapse. Resuscitation must restore oxygen delivery rapidly if irreversible haemorrhagic shock and death is to be prevented. Up to 50% of the patients developing organ failure early after trauma do so in the absence of bacterial infection. Paramedics are trained to minimise on-scene time; a prolonged time to definitive care will increase mortality. Unless the patient is trapped, on-scene interventions should be restricted to Chapter 9: Major trauma 197 control of the airway and ventilation, and stabilisation of the spine. The receiving hospital should be given advanced warning of the impending admission of a severely injured patient. Ambulance personnel should be able to communicate directly with emergency department staff via a talkthrough link. This will include running through drip sets, turning on fluid warmers, and drawing up anaesthetic drugs. Members of the resuscitation team put on protective clothing comprising gloves, plastic aprons and eye protection. The team leader should be a suitably experienced doctor from one of the relevant specialties. Although the first two phases are listed consecutively, they are performed simultaneously. The secondary survey, or head-to-toe examination of the patient, is not started until the patient has been adequately resuscitated. The aim of the primary survey is to look sequentially for immediately life-threatening injuries, in the order that they are most likely to kill the patient. If the airway is obstructed, immediate basic manoeuvres such as suction, chin lift and jaw thrust may clear it temporarily. Manual in-line stabilisation of the neck will minimise movement of the cervical spine during oral intubation, but avoid excessive traction, which may distract a cervical fracture. In the resuscitation room, the cervical spine cannot be deemed undamaged until the patient has been examined by an experienced clinician and/or appropriate radiological procedures have been completed. A reliable clinical examination cannot be obtained if the patient has sustained a significant closed head injury, is intoxicated, or has a reduced conscious level from any other cause. Care of the cervical spine Every patient sustaining significant blunt trauma, particularly above the clavicles, should be assumed to have a cervical spine injury until proven otherwise. Such patients should have their cervical spines immobilised at the accident scene. Significant subluxation of the cervical spine can occur during aggressive chin lift or jaw thrust despite the presence of an appropriate collar. Other reasons for intubating the trauma patient during the resuscitation phase are to optimise oxygen delivery and to enable appropriate procedures to be performed on uncooperative patients. The choice of technique for intubating a patient with a suspected or confirmed cervical spine injury will depend on the indication and on the skill and experience of the individual clinician. If performed with care, tracheal intubation of a patient with a cervical spine injury carries relatively little risk (Crosby 2006). Occasionally, awake fibreoptic intubation may be appropriate, but this will take much longer to achieve and is rarely applicable in the resuscitation phase. Manual in-line stabilisation reduces neck movement during intubation, but excessive axial traction must be avoided. An assistant kneels at the head of the patient and to one side to leave room for the intubator. The McCoy levering laryngoscope may also be useful: it reduces the incidence of grade 3 or worse views to 5%. A variety of videolaryngoscopes are now available, and use of these devices in the trauma setting is likely to become the standard of care. If intubation of the patient proves impossible the airway should be secured by surgical cricothyroidotomy. Standard cannulae may kink and become obstructed, so use a device manufactured specifically for needle cricothyroidotomy. Once intravenous access has been obtained, insert a large chest drain (32 F) in the 5th intercostal space in the anterior axillary line, and connect to an underwater seal drain. Open pneumothorax Cover an open pneumothorax with an occlusive dressing and seal on three sides: the unsealed side should act as a flutter valve. Flail chest Multiple fractures in adjacent ribs will cause a segment of the chest wall to lose bony continuity with the thoracic cage. The immediately life-threatening problem is the underlying lung contusion, which can cause severe hypoxia. Assisted ventilation, via a tracheal tube or by a non-invasive technique, is required if hypoxia persists despite supplemental oxygen. Massive haemothorax A massive haemothorax is defined as more than 1500 mL blood in a hemithorax, and it will cause reduced chest movement, a dull percussion note and hypoxaemia. Cardiac tamponade While not a disorder of breathing, it is logical to consider the possibility of cardiac tamponade while examining the chest, particularly if the patient has sustained a penetrating injury to the chest or upper abdomen. Distended neck veins in the presence of hypotension are suggestive of cardiac tamponade although, after rapid volume resuscitation, myocardial contusion will also present in this way. If cardiac tamponade is diagnosed and the Breathing Look and listen to the chest to confirm that both sides are being ventilated adequately, and measure the respiratory rate. The following chest injuries are immediately lifethreatening and must be diagnosed and treated in the primary survey: r Tension pneumothorax r Open pneumothorax r Flail chest r Massive haemothorax r Cardiac tamponade Tension pneumothorax Reduced chest movement, reduced breath sounds and a resonant percussion note on the affected side, along with respiratory distress, hypotension and tachycardia, indicate a tension pneumothorax. Deviation of the trachea to the opposite side is a late sign, and neck veins may not be distended in the presence of hypovolaemia. Severe haemorrhage from open limb injuries may be controlled with a properly applied tourniquet. In the past, use of tourniquets in this way was discouraged, but recent military experience with blast injuries, in particular, has shown them to be very effective. Until proven otherwise, hypotension should be assumed to be caused by hypovolaemia. Less likely causes include myocardial contusion, cardiac tamponade, tension pneumothorax, neurogenic shock and sepsis. Using forceps, bluntly dissect down into the pleural cavity Insert a finger into the pleural cavity and sweep around to ensure that the lung is clear of the chest wall Select a large chest drain (32 F), remove the trochar, and insert the forceps through the distal side hole. Insert the chest drain into the pleural cavity using the forceps as a guide Suture the chest drain securely to the skin and connect it to an underwater drainage system Obtain a chest x-ray to check for lung expansion and tube position. Needle pericardiocentesis is often unsuccessful because, contrary to traditional teaching, the pericardial blood is often clotted or reaccumulates rapidly once aspirated. Intravenous access Insert two short large-bore intravenous cannulae (14 gauge or larger) into a peripheral vein. Most anaesthetists are confident in inserting central lines but this may not be easy in the hypovolaemic patient and there is a risk of creating a pneumothorax. There is no evidence for use of colloids in the resuscitation phase except, of course, for early use of blood in the exsanguinating patient. Do not use a trochar for chest drain insertion: it can cause serious lacerations of the lung and pulmonary vessels. In both these Chapter 9: Major trauma 201 immediate surgical assessment and is likely to need blood. A sustained reduction in heart rate and increase in blood pressure implies only moderate blood loss (< 20% blood volume). Recently, there has been a trend away from giving large-volume crystalloid fluid challenges in hypovolaemic trauma patients and instead giving blood and blood products much earlier. There is good evidence that tranexamic acid (1 g over 10 minutes given within 3 hours of injury and then an infusion of 1 g over 8 hours) reduces mortality from bleeding in trauma patients. In the absence of obvious external haemorrhage, the likely sources of severe haemorrhage are the chest, abdomen or pelvis. Springing the iliac crests to detect a pelvic disruption is no longer recommended, because it aggravates bleeding. If the patient is going directly to the operating room, rapidly obtain chest and pelvic x-rays. Hypothermia (core temperature < 35 C) is a serious complication of severe trauma and haemorrhage and is an independent predictor of mortality. One study has shown an increase in the incidence of morbid cardiac events in mildly hypothermic patients undergoing a variety of surgical procedures. The oxyhaemoglobin dissociation curve is shifted to the left by a decrease in temperature, thus impairing peripheral oxygen delivery in the hypovolaemic patient at a time when it is needed most. Shivering may compound the lactic acidosis that typically accompanies hypovolaemia, and this may be further aggravated by a decreased metabolic clearance of lactic acid by the liver. The likely mechanisms involved include retarding the function of enzymes in the clotting cascade, enhanced plasma fibrinolytic activity, and reduced platelet aggregation. Mild hypothermia in the perioperative period increases the incidence of wound infection. Resuscitation end points Simply returning the heart rate, blood pressure and urine output to normal does not represent a suitable resuscitation end point for the trauma patient. Hypotensive resuscitation Fluid warming Warm all intravenous fluids, especially blood products. A high-capacity fluid warmer will be required to cope Aggressive fluid resuscitation before surgical control of the bleeding is likely to be harmful: in the presence of active bleeding, increasing the blood pressure with fluid accelerates the loss of red blood cells and may hamper clotting mechanisms. However, older patients and those with a significant head injury will require fluid resuscitation to restore vital organ perfusion. The balance is between the risk of inducing organ ischaemia and the risk of accelerating haemorrhage. If the patient requires urgent induction of anaesthesia and intubation, a quick neurological assessment should be performed first.

As ropivacaine is less lipid-soluble than bupivacaine and less readily penetrates the neuronal myelin sheaths symptoms brain tumor buy 200mg pirfenex visa, C fibres are blocked more readily than A fibres symptoms nausea headache fatigue buy online pirfenex. At high concentrations the blocking effect is similar for both drugs symptoms just before giving birth buy pirfenex visa, but at lower concentrations ropivacaine preferentially blocks C fibres over the faster A fibres section 8 medications buy discount pirfenex line. Ropivacaine has a potential advantage that motor function can be spared (or show earlier recovery) while still achieving sensory blockade medications used for adhd cheap pirfenex online amex, if a suitable concentration of drug is used treatment glaucoma buy pirfenex online now. Combination with a longer-acting agent such as bupivacaine may produce a balance of onset and duration between the two component agents alone. N-dealkylation followed by hydrolysis produces ethylglycine, xylidide and other derivatives that are excreted in the urine. Chapter 33: Local anaesthetic agents 663 sensory blockade similar to that of bupivacaine but motor blockade is slower in onset, less pronounced and shorter in duration. Vasoconstrictors Adrenaline Adrenaline is added to local anaesthetic solutions to reduce vascularity of the area by direct vasoconstriction, and in turn to reduce the systemic uptake of the drug. This has the following effects: r Increased duration of nerve blockade r Greater margin of safety for systemic toxicity r Reduced surgical bleeding Care must be taken to avoid the systemic effects of adrenaline due to systemic uptake. For example, combination with halothane anaesthesia may result in cardiac arrhythmias, especially ventricular excitation and fibrillation. Adrenaline-containing solutions should not be injected in the proximity of end-arteries such as the penile, ophthalmic (central artery of the retina) or digital arteries, as there is no collateral circulation to supplement the supply if vasoconstriction is severe. To minimise the risk of serious systemic actions consider the following: r Avoid hypoxia and hypercarbia. A eutectic mixture is one in which the constituents are in such proportions that the freezing (or melting) point is as low as possible, with the constituents freezing (or melting) simultaneously. The preparation is therefore unusual, as the local anaesthetics are not in aqueous solution, and both agents are in their pure form rather than the hydrochloride preparations used in the solutions. In common with vasopressin, felypressin is a powerful direct-acting vasopressor, but it is safe to use with halothane and has no antidiuretic or oxytocic activity. Additives Glucose Standard solutions of local anaesthetic agents are slightly hypobaric at body temperature and pH, and therefore tend to move upwards in the cerebrospinal fluid away from the gravitational pull. Dextrose (glucose) is added to bupivacaine to increase the density of the solution. Combined with knowledge of the spinal curves and manipulating the position of the patient, this helps to control the distribution of the local anaesthetic. Note that the specific gravity of a substance or solution is the density of that solution relative to the maximum density of water, which occurs at a temperature of 4 C. Hyaluronidase Hyaluronidase, supplied as a white fluffy powder, is used to facilitate the spread of a drug through connective tissues following subcutaneous or intramuscular injection. In addition to promoting the spread of local anaesthetics and other injections, it is also used to promote reabsorption of fluids and blood from extravascular tissues. Preparation and storage are awkward, and the preparations are not widely available. These additives are used to provide a synergistic effect on pain perception by interaction with specific receptors in the afferent pathways. The chiral carbon of bupivacaine (levobupivacaine) is shown in bold (C) Specific pharmacology n-Heptane/aqueous phosphate buffer partition coefficient indicates lipid solubility. Levobupivacaine therefore has 13% more activity than the same dose of racemic bupivacaine. Antiemetic drugs are considered in detail, with specific pharmacology of individual agents to reflect their direct relevance to the practice of anaesthesia. In contrast, the vomiting centre is a complex entity of interconnected areas located in the dorsolateral reticular formation of Fundamentals of Anaesthesia, 4th edition, ed. Anticholinergic drugs are antispasmodic, reducing intestinal tone and inhibiting sphincter relaxation. They also reduce salivary and gastric secretions and so reduce gastric distension. These are the drugs of choice for the treatment of motion sickness and opioid-induced nausea. Hyoscine has been popular for premedication in conjunction with opioids for this reason, and because it possesses a sedative effect. The side effects of anticholinergic drugs are predictable from the known effects of muscarinic cholinergic receptors. In particular, dry mouth and blurred vision can be a problem, and drowsiness is not uncommon. Bronchial secretions become more viscid, but a degree of bronchodilatation is seen (increasing anatomical dead space). Pupillary constriction may be abolished, which removes a useful indicator of depth of anaesthesia. In practice, this requires a tertiary amine structure, and thus physostigmine would be the drug of choice, but it is no longer available. Trifluoperazine is a potent antiemetic, but its antipsychotic effects preclude its routine use for this purpose. Phenothiazines act on the D2 receptors in the chemoreceptor trigger zone in the area postrema, and on M3 receptors in the same way as anticholinergic agents. The major effect of promethazine is antihistaminic, although it has antidopaminergic and antimuscarinic activity that contribute to the antiemetic effect. Nabilone is a synthetic derivative of the naturally occurring tetrahydrocannabinol. Indications for cannabinoid therapy are limited by the side effects of hallucinations, psychosis, dizziness and dry mouth. Fosaprepitant is a prodrug of aprepitant and provides an intravenous alternative with rapid conversion in hepatic microsomes (97% conversion within 15 minutes) by dephosphorylation. Haloperidol and benperidol are primarily used as antipsychotic agents, but haloperidol possesses substantial anticonvulsant activity. Side effects include extrapyramidal phenomena, neuroleptic malignant syndrome and hyperprolactinaemia with gynaecomastia. There are a number of chemically different agents that are antagonists at histaminergic receptors. These are particularly effective in the treatment and prevention of motion sickness. The antiemetic action is centrally mediated, but H1 antagonism may not be the sole mechanism of antiemesis. Ethanolamines (such as diphenhydramine) are potent antihistamines with some anticholinergic activity, which are thought to work at the labyrinth and the neural interface between the labyrinth and the vomiting centre. It has anticholinergic activity, resulting in dry mouth, and can cause tachycardia if given intravenously. Buclizine has a long duration of action but is only available in combined formulation with other drugs. It also contains sodium and phosphate such that it combines two forms of dexamethasone. Miscellaneous antiemetics r Sedatives and anxiolytics often have an antiemetic effect by reducing the psychological component of the nausea. Metoclopramide hydrochloride is a white crystalline salt that is chemically related to procaine. It has antidopaminergic (D2) activity in the chemoreceptor trigger zone and also inhibits the emetic effects of gastric irritants. Extrapyramidal effects (such as oculogyric crisis) are the major potential side effects. Domperidone is a benzimidazole derivative that has both centrally and peripherally mediated effects. Peripherally, domperidone promotes gastric emptying and increases lower oesophageal sphincter tone. These agents may also be useful in promoting gastric transit when this is impaired by diabetic autonomic neuropathy. In pregnancy, most anticonvulsant drugs carry a risk of neural tube defects, teratogenicity and coagulation disorders in the newborn. Counselling, antenatal screening, folate supplements and pre-delivery vitamin K should be considered. The greatest risk to mother and baby, however, is that of the re-emergence of convulsions. In addition, the increase in body water during pregnancy will dilute the concentration of the anticonvulsant agent, thereby reducing its clinical effect. Chloride ions then flow down the concentration gradient into the cell, making it hyperpolarised (more negative) and so less excitable. It has the disadvantage of pronounced sedation, long half-life and active metabolite. The site of action of phenytoin is the fast sodium channel responsible for depolarisation during an action potential. It binds to the channel when it is refractory following opening, and is therefore most effective when repetitive discharges occur. Phenytoin can cause hirsutism, gum hyperplasia, megaloblastic anaemia and fetal malformations. There is the potential for interaction with other drugs, including other anticonvulsants. The high degree of protein binding (85% bound to albumin) results in competition for the binding site with salicylates, phenylbutazone and valproate. Phenytoin metabolism is competitively inhibited by phenobarbital because of enzyme induction in the liver. The same hepatic microsomal enzymes are induced by phenytoin, phenobarbital, steroids, oestrogens and coumarins. Pregabalin has the same mechanism of action but it is claimed to have more specificity for the target receptors, leading to a higher therapeutic index. It also has a role in the management of chronic pain, especially trigeminal neuralgia. It interferes with platelet numbers and function, and can cause neural tube defects. Lamotrigine Lamotrigine stabilises inactive presynaptic sodium channels and so reduces neurotransmitter release. Concentrations are increased by carbamazepine and phenytoin (enzyme inducers) and reduced by valproate. Carbamazepine Carbamazepine is structurally similar to the tricyclic antidepressants and has pharmacological similarities with phenytoin. It acts at voltage-gated sodium channels producing frequency-dependent depression of neuronal activity. With chronic usage, the half-life decreases from 30 to 15 hours due to enzyme induction. It is used for partial epilepsy in combination therapy and as a sole agent for the treatment of the brief infantile spasms of West syndrome. Particular concerns are that a third of patients develop visual field defects, and that it may cause behavioural problems. A Cochrane review which found insufficient evidence of benefit in bipolar disorders noted that a significant proportion of patients had episodes of seizure or syncope (Vasudev et al. Levetiracetam For use alone or as an adjunct for partial seizures and myoclonic seizures. No binding to the usual neurotransmitter agonist sites has yet been found, but it may work at a specific neuronal binding site, resulting in a selective action on epileptogenic neuronal tissue only. Tricyclic antidepressants are chemically related to the phenothiazines, but differ in that the central ring has an additional carbon atom. This changes the shape of the molecule from the planar phenothiazine molecule to a three-dimensional skeleton. Tricyclic antidepressants act by preventing reuptake of neurotransmitter (primarily noradrenaline) into the nerve terminal of monoaminergic neurones. This action is stronger at noradrenergic and serotinergic sites than at dopaminergic sites. Some drugs also act on presynaptic 2-receptors to increase neurotransmitter release.

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If the neonate becomes hypoxic medications look up effective 200 mg pirfenex, hypercapnic or acidotic symptoms 2 weeks after conception buy 200mg pirfenex overnight delivery, pulmonary vasoconstriction can lead to raised right-sided pressures and significant shunting through the foramen ovale medications like lyrica buy pirfenex on line, and reversion to a fetal-type circulation medications 44334 white oblong discount pirfenex 200 mg amex. Fetal and newborn circulation r the placenta supplies oxygen and nutrients to the In addition treatment 8th march discount pirfenex line, calcium metabolism is immature in neonatal myocytes symptoms xanax cheap pirfenex online amex. 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. Each atom has a nucleus (central core) of neutrons and protons, surrounded by a cloud of negatively charged electrons. Carbon provides an example: it has atomic number 6, and therefore six protons, Fundamentals of Anaesthesia, 4th edition, ed. Conventionally, the mass number is shown as a prefix superscript and the atomic number is shown as a prefix subscript, for example 12 C for carbon and 23 Na for 11 6 sodium (11 protons and 12 neutrons). Each orbital shell has a maximum number of electrons, and some stability is conferred when this is achieved. The inert gases are already at their most stable and do not gain or lose electrons. The sodium ion now has the electron configuration of neon, and chloride that of argon. The resultant change in charge causes a strong attraction between the sodium and chloride ions (the ionic bond) which is sufficient to maintain the precise crystalline structure of solid sodium chloride. In contrast with ionic bonding, the atoms share electrons rather than donate them completely. Covalent bonds may be single, double or triple, depending on the number of electron pairs that are shared. Van der Waals forces are the attraction and repulsion of these weakly charged areas to similar areas in neighbouring molecules. Hydrogen bonds A hydrogen bond is a weak electrostatic bond between the positive nucleus of a covalently bonded hydrogen atom in one molecule and the unshared pair of electrons of a highly electronegative atom of another molecule. The hydrogen bonding in water is responsible for the relatively high boiling point (compared with non-polar liquids) and the structure of ice crystals. In this case, the most stable arrangement exists when the additive collects together, leaving as much of the water Van der Waals forces Because electrons are not rigidly fixed relative to the nucleus, but move in characteristic orbitals, the resulting electron cloud has a characteristic shape. Vigorous mixing will provide the energy to break the hydrogen bonds and disperse the fat molecules, temporarily. Looking at this situation in overview gives the impression that the hydrophobic areas and molecules are attracted to each other, but in fact there is little or no attraction at all between the two. It is, in effect, the result of displacement of the hydrophobic molecules by the attraction of water and other hydrophilic molecules. In the case of propofol the lipid is contained within small envelopes (micelles) formed by a layer of molecules. Emulsions Emulsions are used in pharmacology to provide solutions of fat-soluble drugs such as propofol. The strength of ionic and other bonds decreases with the distance between the molecules such that the force of attraction is given by the following formulae: Ionic bond: 1 distance2 1 van der Waals force: force distance7 force In the latter, neighbouring groups of electrons cause repulsion once the distance decreases below a critical level. Serial oxidations and reductions occur in the mitochondrial release of energy in the cytochrome oxidase electron chain. In pharmacology, local anaesthetic agent ionisation by the acceptance of a proton (H+) also constitutes oxidation. Diffusion of molecules in a gaseous or liquid state can also occur between the molecules of a solid. In contrast, the un-ionised form of a drug is required for lipid membrane penetration and hence delivery to the target. When two or more compartments exist together then there will be movement of particles through the interface (permeable) between the compartments. In contrast to the case of simple diffusion, the two compartments in a physiological system are likely to have different affinities for the particles. The coefficient is a dimensionless ratio describing the relative concentrations at equilibrium. Partition coefficients are routinely used to describe the properties affecting distribution of volatile anaesthetic agents. Gases and vapours travel down their partial pressure gradient until the partial pressures are equal. The concentration for a given partial pressure in a particular compartment is determined by the affinity of the constituents of the compartment for the specified molecule. A highly water-soluble molecule such as sodium chloride will have a low oil/water solubility coefficient. Osmosis Osmosis is the passage of a solvent through a semipermeable membrane that separates two compartments having different concentrations of a solute (or solutes) to which the membrane is impermeable. A pure semipermeable membrane is one that is freely permeable to the solvent but impermeable to the solute. In osmosis, an imbalance in the concentration of nonpermeable molecules on two sides of a semipermeable membrane causes movement of the freely permeable solute towards the side of higher concentration. All solutions have an osmotic potential for a given semipermeable membrane and concentration. Osmotic potential may be the result of a single solute, but is usually due to many different molecules. Cell membranes are semipermeable, although ionic transport systems make this picture rather complex. This manipulates the ionic concentrations in the medulla, and therefore water follows ionic concentrations in the tubules and urine output is increased. It is a highmolecular-weight alcohol that remains extracellular, and this produces a negative osmotic potential in the extracellular space that pulls water out of the intracellular space. It is also an osmotic diuretic because it passes readily through the glomerular membrane but is not reabsorbed. Chapter 25: Physical chemistry 545 Structural isomerism Structural (or constitutional) isomerism is the presence of different structures with the same empirical molecular formula. Functional group isomerism In this form of isomerism the functional group changes. For example the movement of the oxygen of an alcohol into the carbon chain produces an ether. Molecules with multiple chiral centres will not form simple superimposable mirror images unless every chiral centre is mirrored Stereoisomerism Stereoisomerism (spatial isomerism) is another form of molecular rearrangement.