Eva L. Feldman, M.D., Ph.D.

• Department of Neurology
• University of Michigan
• Ann Arbor, MI

Even though surgeons will have explained jnc 8 medications cheap lithium 150 mg, it is not uncommon for anaesthetists to find patients who have further questions medications while pregnant purchase lithium 300 mg online. Answer 2 the management varies based on whether there is a patent upper airway or not (patients who have had a laryngectomy) medications and pregnancy buy discount lithium 300 mg online. Principles of resuscitation apply with special consideration of airway patency and management 2c19 medications lithium 300 mg online. S econdary emergency oxygenation: a empt oral tracheal intubation; prepare for difficult tracheal intubation; uncut tracheal tube; advance beyond stoma medications 563 order lithium without a prescription. What are the important considerations in the child with posttonsillectomy bleeding Answer 3 There are three challenges to keep in mind: · Varying (and sometimes severe) degree of blood loss, which is difficult to measure · Ongoing bleeding that can only be controlled under anaesthesia · Blood in the airway in the presence of a full stomach Important factors to discuss include the following: · Life-threatening emergency · Adequate i. S afe anaesthesia for thyroid surgery requires preoperative assessment accounting for specific hazards, an effective plan for intraoperative care and an awareness of the potential postoperative complications. The patient should be euthyroid both clinically and biochemically (by thyroid function testing) before surgery. Look for resting tachycardia or poorly controlled atrial fibrillation as potential indicators of inadequately controlled hyperthyroidism. Infiltrating thyroid carcinoma may make neck movement and tracheal intubation difficult. In severe cases the upper end of the sternum may have to be split at surgery to enable resection. If there are particular concerns regarding the airway, anaesthesia may be induced with the patient in a semirecumbent position. In cases where there is evidence of incipient airway obstruction, tracheostomy under local anaesthesia may be performed. Potential postoperative problems include haemorrhage, airway obstruction, recurrent laryngeal nerve palsy, tracheomalacia and hypocalcaemia. Kumar, Alfred Chua Patients who present for eye surgery are often at the extremes of age. N eonatal and geriatric anaesthesia both present special problems (see Chapters 33 and 31, respectively). S ome eye surgery may last many hours, and repeated anaesthetics at short intervals are often necessary. The anaesthetic technique may influence intraocular pressure (I O P), and skilled administration of either local or general anaesthesia contributes directly to the successful outcome of the surgery. Close co-operation and clear understanding between surgeon and anaesthetist are essential. Risks and benefits must be assessed carefully and the anaesthetic technique selected accordingly. Anatomy and physiology of the eye the perception of light requires function of both the eye and its central nervous system connections. The protective homeostatic mechanisms of the eye are interfered with by anaesthesia in a similar way to the effects of anaesthesia on the central nervous system. I ntraocular pressure is affected by a variety of systemic and ophthalmic factors (Table 38. Functionally it is a balance between the production and removal of aqueous humour (approximately 2. Pressure is distributed evenly throughout the eye and is generally the same in the posterior vitreous body as it is in the aqueous humour, although the pressure is generated in the anterior segment. The aqueous humour is produced by an active secretory process in the non-pigmented epithelium of the ciliary body. Large molecules are excluded by a blood­aqueous barrier between the epithelium and iris capillaries. Carbonic anhydrase catalyses the conversion of water and carbon dioxide to carbonic acid, which passes passively into the aqueous humour. There is a less important hydrostatic element dependent on ocular perfusion pressure. Flow and vascular pressure are controlled by the autonomic nervous system, and autoregulation exists, similar to cerebral blood flow. The sum of the hydrostatic inflow and the active aqueous humour production minus the active resorption and passive filtration must equal zero to achieve balance. The control mechanisms are similar to cerebral blood flow, although there are differences in the anatomy. Oculocardiac reflex the oculocardiac reflex is a triad of bradycardia, nausea and syncope. Classically precipitated by muscle traction, it may also occur in association with stimulation of the eyelids or the orbital floor and pressure on the eye itself. The ophthalmic division of the trigeminal nerve is the afferent limb, passing through the reticular formation to the visceral motor nuclei of the vagus nerve. The risk of development of the oculocardiac reflex is highest in children undergoing squint surgery and in retinal detachment surgery. Treatment requires either a cessation of the stimulus or an appropriate dose of an anticholinergic drug such as atropine or glycopyrronium bromide. The stroma comprises 80%­85% of the corneal thickness and provides the main structural framework. Corneal endothelium is a single sheet of hexagonal cells with poor regenerative capacity. Conditions for intraocular surgery For most intraocular operations, the eye must be insensate, preferably immobile, with intraocular pressure reduced and pupil dilated. A n increase in venous pressure causes fluid to pool in the choroid and may progress to cause rupture of the ciliary artery with prolapse of the iris. O n rare occasions, disastrous expulsive haemorrhage may result in the loss of the entire contents of the eyeball. Drugs used for premedication have little effect on intraocular pressure, and commonly used anxiolytic and antiemetic drugs may be used as preferred. This effect is thought to be caused by the increase in tone of the extraocular muscles and intraocular vasodilatation. Choice of anaesthesia the type of surgery, its urgency and the age and fitness of the patient influence the choice of anaesthesia. Younger patients may sometimes be too anxious for local anaesthesia and are usually managed with general anaesthesia. There is a need to maintain homeostasis in the eye if intraocular surgery is planned. However, all types of ophthalmic surgery have been carried out with local anaesthesia in compliant patients, including repair of ocular trauma. General anaesthesia General anaesthesia is indicated when the patient is unwilling or unable to tolerate local anaesthesia. Patients with dementia, irrespective of the stage of the disease, are generally scheduled for general anaesthesia. The majority of patients in the early stages of the disease tolerate locoregional anaesthesia for routine cataract surgery. It is not uncommon for patients with serious comorbidities which cannot be improved preoperatively to accept the increased risk of death associated with proceeding with surgery and general anaesthesia when the desired outcome is maintenance or improvement of vision. Assessment and preparation S tandard preoperative assessment for patients undergoing general anaesthesia should be carried out for all patients (see Chapter 19). I t is important that the preoperative preparation includes consideration of whether the patient will be able to lie flat for up to an hour without having problems related to cognitive function; becoming uncomfortable, claustrophobic or hypoxaemic; developing myocardial ischaemia; or coughing. Concurrent upper respiratory infection should prompt a cancellation, as coughing and sneezing during the surgery can cause serious difficulties. Long-term anticoagulation presents potential complications that are more relevant to the surgeon or those practising local anaesthesia; however, there are a number of ophthalmic procedures that can be safely carried out without the need to interrupt anticoagulation or antiplatelet therapy. Patients receiving only local anaesthesia are usually not fasted, and this is particularly helpful in managing patients with diabetes mellitus who can receive all their normal medications and achieve be er glycaemic control. Ophthalmic drugs relevant to the anaesthetist O ral, intravenous and topical ophthalmic drugs can all have systemic effects relevant to the anaesthetist; a careful drug history is needed (Table 38. Induction of anaesthesia S mooth induction is particularly important in the ophthalmic se ing. The choice of induction agent is of much less importance than how it is used (see Chapter 4). Airway management the airway may remain inaccessible throughout surgery, and any need to adjust or reposition an airway device during surgery could cause disruption to surgery. Maintenance of anaesthesia There are, in practice, few clinical differences between the effects of different volatile anaesthetic agents or between inhalational and intravenous anaesthesia (see Chapters 3 and 4, respectively). The use of nitrous oxide depends on local availability of medical air and personal preference. Relative hypotension during anaesthesia combined with normoxia and normocapnia provide a soft, well-perfused eye. However, excessive hypotension may prompt questions from the ophthalmologist because of the absence of flow in the retinal arteries during some ocular procedures. Maintenance of an adequate blood pressure is a greater challenge in elderly patients in the absence of significant surgical stimulation. There is li le, if any, alteration in body fluid status, and care should be taken not to be too liberal with i. O phthalmic surgery is performed commonly on patients with diabetes because of complications of the disease. I f general anaesthesia is required, local protocols must be followed (see Chapter 20). A nalgesia requirements are based on the intraoperative use of a short-acting opioid and paracetamol. Local anaesthesia with a longer-acting local anaesthetic drug is particularly useful intraoperatively. The combination of antiemetic agents from different classes is more effective than a single antiemetic agent (see Chapter 7). However, although rare, serious complications of ophthalmic local anaesthesia can and do occur. A detailed knowledge of the anatomy of the eye and the relevant pharmacology is important. Relevant anatomy for ophthalmic regional techniques the orbit is a four-sided irregular pyramid with its apex pointing posteromedially and its base anteriorly. The annulus of Zinn is a fibrous ring which arises from the superior orbital fissure. These muscles arise from the annulus of Zinn and insert on the globe anterior to the equator to form an incomplete cone. I t is very important that the needle should not be inserted too far, close to the annulus, where the vital nerves and vessels are tightly packed. The ophthalmic division of the oculomotor nerve divides into superior and inferior branches before emerging from the superior orbital fissure. The superior branch supplies superior rectus and levator palpebrae superioris muscles. The inferior branch divides into three to supply the medial rectus, inferior rectus and inferior oblique muscles. The abducent nerve emerges from the superior orbital fissure beneath the inferior branch of the oculomotor nerve to supply the lateral rectus muscle. The trochlear nerve (I V) courses outside the cone but then branches and enters the cone to supply the superior oblique muscle. A n incomplete block of this nerve leads to retained activity of the superior oblique muscle. This nerve emerges from the foramen spinosum at the base of the skull, anterior to the mastoid and behind the earlobe. I t passes through the parotid gland before crossing the condyle of the mandible and then passes superficial to the zygoma and malar bone before its terminal fibres ramify to supply the deep surface of the orbicularis oculi. The facial nerve also supplies secretomotor parasympathetic fibres to the lacrimal glands and glands of the nasal and palatine mucosa. The capsule extends 5­8mm behind the limbus and extends posteriorly to the optic nerve and as sleeves along the extraocular muscles. J ust before entering the orbit, it divides into three branches: lacrimal, frontal and nasociliary. I t emerges through the superior orbital fissure between the superior and inferior branches of the oculomotor nerve and passes through the common tendinous ring. Two long ciliary nerves give branches to the ciliary ganglion and, with the short ciliary nerves, transmit sensation from the cornea, iris and ciliary muscle. S ome sensation from the lateral conjunctiva is transmi ed through the lacrimal nerve and from the upper palpebral conjunctiva via the frontal nerve. The superomedial and superotemporal quadrants have abundant blood vessels, but the inferotemporal and medial quadrants are relatively avascular and are safer places to insert a needle or cannula. The globe occupies almost 50% of the orbital volume at birth and 33% at 4 years, whereas the adult globe only fills 22% of the orbital volume. Nomenclature of blocks the terminology used for ophthalmic block varies, but the widely accepted nomenclature is based on the anatomical location of the needle tip. Multiple communications exist between the two compartments, and it is difficult to differentiate whether the needle is intraconal or extraconal during insertion. I njected local anaesthetic agent diffuses easily across compartments and, depending on its spread, anaesthesia and akinesia may occur. A combination of intraconal and extraconal block is described as a combined retroperibulbar block.

Once successful engraftment of donor cells is established symptoms ketoacidosis cheap lithium 300 mg on-line, the recipient is a genetic chimera treatment 3 nail fungus safe 150 mg lithium. Donor cells are monitored by following donor-specific alleles of polymorphic markers in the recipient blood and bone marrow medications prolonged qt lithium 300 mg order fast delivery. The second part of the testing process is the engraftment analysis medications ok for pregnancy buy lithium, which is performed at specified intervals after the transplantation symptoms urinary tract infection order 300 mg lithium fast delivery. Copy number and epigenetic markers are usually labor-intensive and have limited alleles if they are not done on a genomewide scale. With the living family member, Prince Philip, the great nephew of the last queen, the scientist may be able to tell whether the bones belong to the Russian royal family. Copy-number variants and epigenetic markers are usually labor-intensive and have limited alleles if they are not done on a genomewide scale. If the assay is performed for the four common pathogenic variants representing 99% of the pathogenic variants, 99% 3 99% 5 98% of carrier couples could be detected. If the assay is performed for the two most common pathogenic variants representing 97. In practice, the way in which analytic sensitivity is calculated varies according to the laboratory, with differing replicates and matrices. In clinical molecular practice, analytical sensitivity is usually calculated as number of true positive samples with positive test results/number of true positive sample 5 90/(10 1 90) 5 90%. Analytical specificity refers to freedom from interference by any element or compound other than the analyte. In clinical molecular practice, analytical specificity calculated as number of true negatives with negative test results/number of true negative samples 5 80/(20 1 80) 5 80%. Disease 1 Test 1 2 90 10 2 20 80 Therefore, the analytical specificity of this assay for TayÀSachs disease is 80%. Accuracy refers to the extent to which all measurements agree with the true value of what is being measured. In clinical molecular practice, analytical accuracy is calculated as (number of true positives with positive test results 1 number of true negatives with negative test results)/(number of true positive 1 number of true negative) 5 (90 1 80)/(100 1 100) 5 85%. Clinical negative predictive value is defined as the probability that a negative test result is correct. Assuming analytic sensitivity and a specificity of 100%, a false negative result will occur because the mutation present is not being tested by the laboratory. About 5% of pathogenic variants will not be identified by the assay testing the two pathogenic variants. Since the carrier risk frequency is 1 in 127, there are approximately 20 carriers in 2540 Ashkenazi Jews. A lot of overlapped short sequence reads will be assembled together on the basis of their overlapping areas as shown in the figure. The mean mapped read depth (or mean read depth) is the sum of the mapped read depths at each reference base position divided by the number of known bases in the reference. The mean read depth metric indicates how many reads, on average, are likely to be aligned at a given reference base position. Deep sequencing refers to sequencing a genomic region multiple times, sometimes hundreds or even thousands of times. At higher levels of coverage, each base is covered by a greater number of aligned sequence reads, so base calls can be made with a higher degree of confidence. Sequencing coverage describes the average number of reads that align to , or "cover," known reference bases. Therefore, the coverage of this region is unclear according to the figure in the question. The left side of the figure it showed the reads were aligned to the build 37 human reference sequences. Roche 454 sequencing can produce read lengths approximately 400À700 bp, while Illumina genome sequencing can generate read length of only around 90 bp. Therefore, Sanger sequencing has the highest accuracy and remains the gold standard for sequencing. This step includes the targeted genomic region enrichment (library preparation) if a panel or exome sequencing is the goal. First, reads are aligned onto an available reference genome, then variable sites are identified and genotypes at those sites are determined. Each read is aligned independently, causing many reads that span in/dels to be misaligned. The raw basecalling quality scores often co-vary with features like sequence technology, machine cycle and sequence context and, thus, cannot reflect the true base-calling error rates. Therefore, reading deeps, location of variants in the fragments, and ratio of the forward to reverse reading usually are all monitored to assess the accuracy of the detections to decrease the false positive findings. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Regions of sex-specific hypo- and hyper-recombination identified through integration of 180 genetic markers into the metric physical map of human chromosome 19. The responsibility of genetic test quality regulation is often divided among several regulatory agencies, which safeguard different elements of the testing process. This introduction is an overview of the regulatory agencies for clinical genetics laboratories. Then, each participating laboratory receives a report of Self-assessment Questions for Clinical Molecular Genetics. Professional certification also requires that clinical molecular geneticists participate in continuing education to maintain and develop 79 © 2019 Elsevier Inc. This professional organization has more than 1600 board-certified clinical and laboratory genetics professionals. Its mission is to prevent workrelated injuries, illnesses, and deaths by issuing and enforcing rules for workplace safety and health. These people often had trouble getting health insurance because of a medical problem they had before they tried to buy health insurance (called a "preexisting condition"). This 2008 federal law protects individuals from genetic discrimination in health insurance and employment. The law also prohibits most employers from using genetic information for hiring, firing, or promotion decisions and for any decisions regarding terms of employment. This means that the numbers do not carry other information about health care providers, such as the state in which they live or their medical specialty. The protocol received ´ from bioMerieux was for 20-µL total volume for each reaction. A clinical molecular genetic scientist has been working in a start-up company for 2 months. He has been purchasing reagents and writing policies and procedures for this new laboratory. Checking the quality of new lots and new shipments of reagents against old ones C. He checked the identifiers of the sample on the requisition form and the tube to make sure the identity of the sample matched. A courier picked up a peripheral-blood sample (lavender) from a local obstetrician/gynecologist (Ob/Gyn) practice for cystic fibrosis testing in the main hospital. According to procedure, he sends samples to the cytology laboratory in the same hospital for hybridization, then takes the slides back for analysis. According to procedure, she sends samples to the cytology laboratory in the same hospital for hybridization, then takes the slides back for analysis. The specimens were treated as regular clinical samples, and were signed out in the electronic reporting system in the laboratory. The specimens were treated as regular clinical samples and were signed out in the electronic reporting system in the laboratory. He started to investigate the reason while sending the samples to a reference laboratory. One of the ideas was to send the specimens to the reference laboratory as clinical samples. A start-up clinical molecular genetics laboratory in the state of Arizona welcomed its first on-site inspector on a Monday morning. Agents that are likely to cause serious or lethal human disease for which preventive or therapeutic interventions are not usually available (high individual risk and high community risk). Agents that are associated with human disease that is rarely serious and for which preventive or therapeutic interventions are often available D. Agents that are associated with serious or lethal human disease for which preventive or therapeutic interventions may be available (high individual risk but low community risk). Agents that are associated with human disease that is rarely serious and for which preventive or therapeutic interventions are often available. This makes it harder and harder for the body to fight infections and other diseases. The Ebola virus causes an acute and serious illness that is often fatal if left untreated. The latter occurred in a village near the Ebola River, from which the disease takes its name. Rabies disease is most often transmitted through the bite of a rabid animal such as raccoons, skunks, bats, and foxes. He found that one of the procedures stated that a designee of the director would review and assess instrument and equipment maintenance and function-check records semiannually. He should check the thermal cyclers from the same manufacturer against each other at least once a year. He should check the thermal cyclers from the same manufacturer against each other at least twice a year. He planned to review all the procedures and policies in the laboratory in the first month. He found that one of the procedures stated that a designee of the director would check the 20 thermal cyclers against each other once a year. Since the gender of the specimen was unknown, the director was concerned about whether there was a gross deletion or a mutation in the primer region leading to allelic drop. He called a director at another institute to discuss the result before finalizing it. He planned to review all the procedures and policies in the laboratory in the first 2 months. A, a newly board-certified molecular geneticist, started to work for a hospital 10 days ago. The laboratory support team assessed the situation and suggested the purchase of a new remote drive or the deletion some files in the current hard drive to free some space. D, a director of a clinical laboratory in Wisconsin, found that a lot of restriction enzymes in the laboratory had passed the expiration date. It would be a huge waste to throw them away, so he tested the enzymes with positive controls, negative controls, and 10 previous patient samples. All the results were correct, so he decided to keep using those enzymes clinically. When reviewing the procedures and policies in the laboratory, he found that the laboratory only checked new reagent lots against old reagent lots, but not against new reagent shipments in the same lot. A changed the procedure to check new reagent lots and new shipments against old reagent lots and old shipments. G that the Eppendorf thermal cycler had had a problem and that a clinical engineer took it a few days ago. It is a Phase 0 deficiency to use newly fixed instruments/equipment before performance verification. It is a Phase I deficiency to use newly fixed instruments/equipment before performance verification. G felt that using newly fixed instruments/ equipment before performance verification did not feel right. Last month the laboratory moved from the main hospital to a remote facility with the rest of the department of pathology. Competency assessed for analysts within 12 months prior to restarting patient testing D. Method of performance specifications verified, as applicable, within 30 days prior to restarting patient testing C. Using reference materials or other materials with known concentrations or activities B. Repeating measurement of samples at varying concentrations or activities within-run and between-run over a period of time D. The test is performed by the clinical laboratory, while the test procedure was created by another laboratory. How frequently should a director of a clinical molecular laboratory review the maintenance and function check records of centrifuges, according 64. He planned to review all the procedures and policies in the laboratory in 2 months. He found that the quality management procedure stated that a designee of the director would review this procedure biennially. He found that the quality management procedure stated that the competency assessment records should be kept for 1 year. How frequently should a clinical molecular laboratory retain the competency assessment records He found that the quality management procedure stated that the quality control records should be kept for 1 year. How frequently should a clinical molecular laboratory retain the quality control records Investigation of the laboratory by a government entity or other oversight agency B. Discovery of actions by laboratory personnel that violate national, state, or local regulations C.

Ventricular arrhythmias the threshold for arrhythmias is reduced by hypokalaemia symptoms lymphoma 300 mg lithium order amex, hypomagnesaemia and hypocalcaemia symptoms definition cheap lithium 300 mg mastercard. The abrupt onset of ventricular tachycardia or ventricular fibrillation after moving the patient from the operating table to the bed may herald coronary aeroembolism red carpet treatment order genuine lithium on line. However symptoms 0f gallbladder problems buy lithium 300 mg visa, there may be some advantages to managing these patients on separate extended recovery units treatment for 6mm kidney stone order lithium overnight. I n such instances the interval between admission and weaning from mechanical ventilation can usually be considerably shortened. This so-called fast-track approach may be associated with earlier discharge and reduced morbidity from unnecessarily prolonged sedation and mechanical ventilation of the lungs. Care must be taken to prevent inadvertent injury and avulsion of indwelling tubes, catheters and cannulae. Mechanical ventilation, drug therapy and haemodynamic monitoring should be continued throughout transfer. Regardless of location, there should be a well-practised routine for the care of patients after surgery. Usually, ventilation of the lungs and full cardiovascular monitoring are recommenced immediately. The principles of care in this phase are similar to those described for the period of anaesthesia after termination of bypass. The principles underpinning the management of patients in the first few hours after cardiac surgery are the maintenance of haemodynamic stability, adequate pulmonary gas exchange, normal acid­base homeostasis, haemostasis and renal function. I n the uncomplicated patient, sedation can be discontinued 3­4h after admission and the patient weaned from mechanical ventilation. Criteria for tracheal extubation include the following: · Awake, orientated, responds to commands · Temperature greater than 35. However, excessive bleeding (>150mlh ­1) should be considered abnormal and prompt further assessment. Blood component administration is often required (fresh frozen plasma, cryoprecipitate or platelet concentrate). The use of factor concentrates such as prothrombin complex concentrate (instead of fresh frozen plasma) or fibrinogen concentrate (instead of cryoprecipitate) may also be considered, especially in patients who are already fluid overloaded. Temperature and acid­base balance should be normalised and anaemia corrected, as low haemoglobin concentration is also associated with increased bleeding. I n contrast, bleeding in the se ing of normal coagulation should prompt consideration of early surgical re-exploration. However, it should be borne in mind that both resternotomy and massive transfusion are associated with significantly increased morbidity and mortality. I n some instances in which chest tube drainage is inadequate, the accumulation of blood within the chest may lead to haemodynamic collapse secondary to cardiac tamponade. Falling arterial blood pressure and rising central venous pressure should be considered to be due to tamponade until proved otherwise. Analgesia Pain after sternotomy is limited because surgical wiring of the sternum during closure prevents excessive bone movement and muscle injury is not a feature. Patients tend to complain more about pain from chest drain sites and leg or arm wounds (from harvesting of the saphenous vein or radial artery). Regular paracetamol should be administered, and morphine by infusion or nurse-administered bolus is often required. I ntercostal drains are usually removed on the day after surgery, and analgesia for their removal can be provided by nitrous oxide/oxygen (Entonox) inhalation. International consensus statement on the peri-operative management of anaemia and iron deficiency. You are asked to anaesthetise a 74-year-old man with critical left main stem stenosis for urgent coronary artery bypass graft surgery. Answer 1 Consider detailed history, examination, investigations concentrating on cardiovascular disease, including angiogram (degree of stenosis and other coronary disease) and echocardiography (ventricular function and valvular disease). D iscuss induction of anaesthesia in critically ischaemic patients, including intra-aortic balloon pump and readiness of the whole team. Postoperative care and weaning from ventilation, haemorrhage and requirement for inotropes. Discuss how you would manage a patient who was unable to be weaned off extracorporeal support. This has led to the establishment of obstetric anaesthetic assessment clinics in many hospitals. Remote site work in a dynamically changing environment can be challenging, however obstetric anaesthesia offers the opportunity to make a key difference to safety and the overall experience of women around labour and delivery. Anatomy and physiology of pregnancy the obstetric anaesthetist must understand maternal adaptation to pregnancy in order to manipulate physiological changes after general anaesthesia or regional analgesia and anaesthesia in such a way that the condition of the neonate at delivery is optimised. The physiological changes of pregnancy are exaggerated in multiple pregnancy which is increasing in incidence after the success of assisted, conception. I t is secreted in increasing amounts during the second half of the menstrual cycle to prepare the woman for pregnancy. A fter conception, the corpus luteum ensures adequate blood concentrations until placental secretion is adequate. Aortocaval compression When a pregnant woman lies supine, arterial pressure decreases because the gravid uterus compresses the inferior vena cava, reducing venous return and therefore cardiac output. At term the vena cava is completely occluded in 90% of pregnant women, and stroke volume may only be 30% of that of a non-pregnant woman. The aorta is also often compressed, so femoral arterial pressure may be lower than brachial arterial pressure; this is the main cause of a reduction in uterine blood flow. The combination of both effects is known as aortocaval compression, which becomes clinically significant from around 20 weeks. Physiological compensation occurs via sympathetic stimulation and collateral venous return via the vertebral plexus and azygous veins. The effect of aortocaval compression varies from asymptomatic mild hypotension to cardiovascular collapse and is usually prevented or relieved by left tilt or wedging, although complete lateral position is required in some cases. I n the event of cardiac arrest the uterus may be manually displaced to the left if a wedge or tilting table is not present. There is a considerable increase in blood flow to the skin, resulting in warm, clammy hands and feet. This vasodilatation, together with that in the nasal mucosa, helps fetoplacental unit. The oxyhaemoglobin dissociation curve of haemoglobin F (HbF) is to the left of that for HbA. Placental exchange of oxygen is regulated mainly by a change in oxygen affinities of HbA and HbF caused principally by altered hydrogen ion and carbon dioxide concentrations on both sides of the placenta. This substantial reduction, combined with the increase in tidal volume, results in large volumes of inspired air mixing with a smaller volume of air in the lungs. The composition of alveolar gas may be altered with unusual rapidity and alveolar and arterial hypoxia develop more quickly than normal during apnoea or airway obstruction. O verall several changes occur in pregnancy that contribute to airway difficulty and an increased rate of development of hypoxaemia during apnoea (Box 43. Glycosuria often occurs because of decreased tubular reabsorption and the increased load. The renal pelvis, calyces and ureters dilate as a result of the action of progesterone and intermi ent obstruction from the uterus, especially on the right. Gastrointestinal changes Gastrointestinal changes also stem from the effects of progesterone on smooth muscle. A reduction in lower oesophageal sphincter pressure occurs before the enlarging uterus exerts its mechanical effects (an increase in intragastric pressure and a decrease in the gastro-oesophageal angle). These mechanical effects are greater when there is multiple pregnancy hydramnios or morbid, obesity. Together with the sphincter pressure changes, this makes regurgitation and inhalation of acid gastric contents more likely to cause pneumonitis in pregnancy. Gastrointestinal motility decreases but gastric emptying is not delayed during pregnancy. Pain, anxiety and systemic opioids (including epidural and subarachnoid administration of opioids) aggravate gastric stasis. S mall and large intestinal transit times are increased in pregnancy and may result in constipation. Coagulation and fibrinolysis generally return to pre-pregnant levels 3­4 weeks postpartum. Thromboelastography may be useful to assess platelet function and clot stability, but its use in pregnancy is unproven. These valveless veins of Batson form collaterals and become engorged as a result of aortocaval compression during a uterine contraction or secondary to raised intrathoracic or intra-abdominal pressure. The dose of local anaesthetic for epidural analgesia or epidural/subarachnoid anaesthesia is reduced by about one third for the following reasons: · Spread of local anaesthetic in either the subarachnoid or epidural space is more extensive as a result of the reduced volume. The onset of nerve block is more rapid, and human peripheral nerves have been shown to be more sensitive to lidocaine during pregnancy. D uring contractions, particularly in the second stage, the pressure in the subarachnoid and epidural space becomes very high. Consequently, it is advised not to advance an epidural needle, insert epidural catheters or administer epidural top-ups at that time. Even if precautions are taken to prevent it, intermi ent aortocaval compression always occurs in association with maternal movement. Pain pathways in labour and caesarean section Pain pathways in labour and caesarean section the afferent nerve supply of the uterus and cervix is via A and C fibres, which accompany the thoracolumbar and sacral sympathetic outflows. The pain of the first stage of labour is referred to the spinal cord segments associated with the uterus and the cervix, namely T10­12 and L1. When anaesthesia is required for caesarean section, all the layers between the skin and the uterus must be anaesthetised. I t is important to remember that the most sensitive layer is the peritoneum, and therefore the block should extend up to at least T4 and also include the sacral roots (S 1­5) to cold and T5 to touch. The placenta the placenta is both a barrier and link between the fetal and maternal circulations. I t consists of both maternal and fetal tissue ­ the basal and chorionic plates, separated by the intervillous space. The two circulations are separated by two layers of cells ­ the cytotrophoblast and the syncytiotrophoblast. Placental blood flow depends on the perfusion pressure across the intervillous space and the resistance of the spiral arteries. Functions of the placenta Transport of respiratory gases Transport of respiratory gases is the most important function of the placenta and was described earlier. O estrogens are secreted by the placenta and have a role in breast and uterus development. Immunological the placenta modifies the fetal and maternal immune system so that the fetus is not rejected. I mmunoglobulin G (I gG) is transferred across the placenta and confers some passive immunity but may also produce disease. Placental transfer of drugs the barrier between maternal and fetal blood is a single layer of chorion united with fetal endothelium. Placental transfer of drugs occurs, therefore, by passive diffusion through cell membranes, which are lipophilic. However, this membrane appears to be punctuated by channels that allow transfer of hydrophilic molecules at a rate that is around 100,000 times lower. The rate is directly proportional to the materno­fetal concentration gradient and the area of the placenta available for transfer, and inversely proportional to placental thickness. Factors determining placental transfer Materno­fetal concentration gradient D rug transfer occurs down a concentration gradient in either direction. The maternal drug concentration depends on the route of administration, dose, volume of distribution, drug clearance and metabolism. The highest concentration is achieved after intravenous administration, although epidural and intramuscular administration result in similar concentrations. Fetal drug concentration depends on the usual factors of redistribution, metabolism and excretion. The fetus eliminates drugs less effectively because its enzyme systems are immature. The distribution differs because of the anatomical and physiological organisation of the fetal circulation; for example, drugs accumulate in the liver because of the umbilical venous flow to the liver and are metabolised before distribution. The relatively high extracellular fluid volume explains the large volumes of distribution of local anaesthetics and muscle relaxants. Molecular weight and lipid solubility the placental membrane is freely permeable to lipid-soluble substances, which undergo flow-dependent transfer. The majority of anaesthetic drugs are small (molecular weights of less than 500 D a) and lipid soluble and so cross the placenta readily. Protein binding A dynamic equilibrium exists between bound (unavailable) and unbound (available) drug. Many basic drugs are bound to 1-glycoprotein, which is present in much lower concentrations in the fetus than in the adult. Degree of ionisation the placental membrane carries an electrical charge; ionised molecules with the same charge are repelled, whereas those with the opposite charge are retained within the membrane. The rate of this permeability-dependent transfer is inversely proportional to molecular size. S ize limitation for polar substances begins at molecular weights between 50 and 100 D a.

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