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In moderate to blood pressure chart senior citizens buy discount zestoretic 17.5 mg severe ptosis with a moderate levator action arteria 2000 buy 17.5 mg zestoretic mastercard, levator resection can be carried out by a conjuncti val approach or anterior technique heart attack 80s song order zestoretic amex. A 10 mm resection is minimal for congenital ptosis and maximal for senile pto sis blood pressure high in morning order zestoretic online from canada. Plication of the superior levator aponeurosis is currently being evaluated in moderate ptosis for a better functional result blood pressure below 100 order zestoretic 17.5mg free shipping. In the Blaskovics operation the upper lid is doubly everted over a Desmarre lid retractor. An incision is then made Surgery is the treatment of choice and is carried out through the conjunctiva near the tarsal border and dissected between 3 and 5 years of age if the ptosis is partial, but if back to the fornix (Fig. A button-hole incision is the visual axis is covered at least a temporary procedure made on the temporal side and the scissors passed across, should be carried out as soon as possible to avoid sensory just above the aponeurosis, to the nasal side. The type of surgery is inserted, one blade being above and the other below the performed is determined by the amount of ptosis, the leva aponeurosis of the levator which is cut free and drawn tor action and associated anomalies such as a Marcus Gunn downwards; l or 2 mm of the upper border of the tarsus is phenomenon. The levator horns are identifed with traction and the Fasanella–Servat operation is indicated for cases cut with a pair of scissors. The aponeu rosis should be carefully identifed, the lid everted and the conjunctiva above the tarsal border ballooned with saline. A small buttonhole incision is made through the conjunctiva on the temporal side and blunt scissors passed across, watching the blades through the thin conjunctiva. A ptosis clamp is passed as the scissors are withdrawn with one blade under the conjunctiva and the other on top of the aponeurosis. With the aponeurosis in the ptosis clamp and all tissues freed from both surfaces, the horns should be carefully incised so as not to damage the superior oblique tendon or the lacrimal gland. Three double-armed 6-0 chromic gut sutures are passed through the aponeurosis from below upwards and tied securely with three knots. The upper eye lid is maintained in a position of double eversion to expose the conjunctival the outer layer of the tarsus parallel to the lid border and surface of the lid and the region of the superior fornix, and this is achieved approximately 4 mm from the lid margin. These sutures by the use of Desmarre eyelid retractor which presses on the skin surface are tied. The palpebral conjunctiva is incised in the region of the upper gut sutures are added to ensure frm fxation of the entire border of the tarsal plate and three double-ended silk sutures (with the loop aponeurosis. A good fold is produced with a 6-0 silk suture of each suture on the inner surface of the conjunctiva) are inserted into the upper edge of the incised conjunctiva so that this portion of the con for adults and vicryl or chromic catgut for children. To junctiva is retracted into the region of the superior fornix with exposure of produce a frm scar each suture should pass through the the underlying superior palpebral muscle and levator tendon. A 4-0 silk Frost-type suture is inserted below the lash line for at least 10 mm and brought tied with three knots. The excess aponeurosis is excised and up to be passed through the skin just below the brow. A frm these sutures are passed completely through the upper edge dressing is applied. They are then Whitnall’s sling procedure: this procedure is used to carried along the anterior surface to emerge through the correct severe ptosis with levator function of 3–5 mm. The conjunctiva is closed with a con underlying levator muscle are then sutured to the superior tinuous 6-0 absorbable suture such as chromic catgut or tarsal plate. Levator plication: In cases of mild to moderate ptosis, Anterior approach levator aponeurotic resection: the the levator instead of being resected can be simply double anterior approach is recommended in patients who require breasted over itself to produce a good result. In the Everbusch technique the line of include less time, simpler technique and no extensive dis incision is in the future lid fold. Excess skin to be re tages of this technique are that there is much more lid moved later should be taken from the upper lip of the lag and lagophthalmos as compared to resection and poor wound. The skin of the lid is held taut, the incision made results in moderate to severe ptosis. It should be remem with a razor blade, and the dissection carried upwards and bered that levator plication can give good results only if the downwards under the obicularis muscle to expose the levator function is good/fair. A vertical incision is made through the sep ing the levator muscle and putting three mattress sutures tum with a knife and spread open with a small pair of scis through the upper border of the tarsus and at appropriate sors. Pressure on the globe usually causes the pre-aponeurotic vertical height of the levator. Once the proper lift is obtained then one suture is passed medially and one laterally to give a proper lid contour. Frontalis suspension: When the levator muscle is intact but the function is poor (3 mm or less), strengthening by resection of the levator is not recommended and the lid is then suspended from the frontalis. This may be carried out by the use of sutures, fascia lata sling or silicon bands. The operation is useful for young children as a tempo rary measure until they are able to cooperate better as they grow older. A 4-0 Supramid extra suture with swedged-on needles incision is made midway between the two, some 16 mm facilitates easy passage through the outer layers of the tar above them. After attachment to the tarsus, the needles are removed ings in the lid and then upward emerging with two ends in and the two sutures are carried upwards through the deeper each of the openings above the brow. One end of the fascia layers of the lid with a one-half curved cutting needle is cut off and the other emerges at the central incision. The to emerge through the wound made above the brow fascia must lie deep in the lid tissue and be drawn up quite (Fig. These sutures are deep enough to prevent tightly because there is a tendency towards undercorrection. The fascial strips are secured with 5-0 chromic catgut or Infection of the suture bed is an annoying complication vicryl at each brow incision. The forehead wounds are and the suture should be guarded carefully, kept away from closed with deep mattress sutures followed by a Frost-type the skin and lashes during surgery and the wound in the 4-0 silk suture in the lower lid. To reduce If after these operations it is found that when the eyeball the scar on the forehead, a deeply placed mattress suture of is raised, the skin of the upper lid falls in an unsightly fold 6-0 silk or Mersilene brings the muscle, fascia and skin over the lashes, a horizontal strip of skin of suitable width together. A short deep incision is made 5 mm in the skin of the eyelid in the normal position. The third Acquired Ptosis Acquired ptosis is usually unilateral and its cause needs to be identifed so that appropriate therapy can be instituted. Neurogenic ptosis: It may be part of the symptom complex involving the entire third nerve at any point in its path, or rarely it may be due to affection of the branch sup plying the levator. Isolated ptosis without other signs of oculomotor paralysis may result from disease of the supra nuclear pathways (see Chapter 31, Diseases of the Nervous System with Ocular Manifestations). Horner syndrome is a common cause of neurogenic ptosis and is accompanied by miosis and anhidrosis, as sympathetic innervation is reduced. It may also be due to direct injury of the muscle or its nerve supply, as by wounds or fractures. In Chapter | 28 Diseases of the Lids 465 all neurogenic ptosis, the patient should be reviewed peri odically on conservative management to allow for any spontaneous recovery and for the defcit to stabilize. In complete paralysis of the third nerve, surgery is usually contraindicated till strabismus has been corrected, since if the lid is raised in these cases diplopia becomes manifest. Two techniques may be applied: (i) if the levator is not completely paralysed this muscle may be resected as described above and (ii) if the levator is paralysed, the action of the frontalis muscle may be utilized in raising the lid. Ophthalmology 2014: ment of the primary disorder should be undertaken frst, 1272–1277. Myasthenia gravis is a disease characterized by gener Mechanical ptosis occurs when tumours or infamma alized muscular weakness and rapidly developing fatigue tions weigh down the lid and cause it to droop. Treatment of the muscles due to an auto-immune disorder in which is that of the cause. Attempts can be made to modify the defective Benign Growths immune mechanism with corticosteroids, immunosuppres sives, plasmapheresis and thymectomy. The symptoms these include xanthelasma, molluscum, warts, naevus, fuctuate and, after a short rest, recovery follows rapidly in angioma and other tumours common to the skin and cuta the early stages. The ptosis is nearly always bilat Small clear cysts frequently occur among the lashes in eral and is increased by prolonged fxation or attempts to old people, due to the retention of secretion of Moll glands. Ophthalmoplegia externa, partial or complete, occurs in 50% of the cases, but the intrinsic Xanthelasma or Xanthoma muscles are not affected. Nystagmoid jerks are not uncom Xanthelasma or xanthoma are slightly raised yellow mon. Remarkable temporary improvement in the action of plaques, most commonly found in the upper and lower lids the muscles is obtained by injections of prostigmin or edro near the inner canthus, and often symmetrical in the two phonium (Fig. Thus, women, and are sometimes associated with diabetes and acetylcholine briefy accumulates in greater than normal hypercholesterolaemia. They grow slowly, and require amounts in the ganglia, post-ganglionic sympathetic nerve treatment only on account of the disfgurement. The resultant increase in acetylcholine available at the receptor sites leads to an improvement in the muscular Naevus or Mole function, confrming the diagnosis. Usually pigmented, this may occur on the lids, generally Aponeurotic ptosis is involutional, and is due to a affects the margin and involves both the skin and conjunc weakness or disinsertion of the levator palpebrae superi tiva. Two may be symmetrically situated on the lids of oris aponeurosis from the anterior surface of the tarsus. The microscopic appearance is character of a high lid fold with good levator action. Sometimes the istic, consisting of naevus cells, often arranged in an alveo fold may be absent. They may grow at puberty but very rarely re-insertion of the levator aponeurosis to the anterior sur take on malignant proliferation. They may be removed by face of the tarsus and appropriate resection of the levator. The former are bright red or port-wine coloured spots composed of dilated capillaries. The latter consist of dilated and anas tomosing vascular spaces lying in the subcutaneous tissue having all the characteristics of erectile tissue, and are not infrequently strictly localized as if partially encapsulated. They appear bluish when seen through the skin and form swellings, which become bigger and increase in size on venous congestion as on crying or lowering the head. Haemangioma often follows the distribution of the frst of large doses of systemic steroids for several months under and second divisions of the trigeminal nerve. Superfcial radiotherapy Weber syndrome capillary haemangioma of the face (80–120 kV) may be given in doses of 100–200 rad (Fig. Injection of sclerosing solutions is discour meninges, causing homonymous hemianopia or epilepsy. The intracranial lesion may be diagnosed radiographically since there are often calcareous deposits underlying the Neurofbromatosis cerebral cortex. Telangiectases and small haemangiomata usually disap Neurofbromatosis is also known as elephantiasis neuroma pear by the age of 5–6 years, and may well be left alone. If they increase in size, cause amblyopia or strabismus, the lids and orbit may be affected. The swollen vision, cosmetic surgery can be undertaken after the child lid and temporal region form a characteristic picture in is 3–5 years of age. The hypertrophied nerves can lone and 6 mg betamethasone sodium phosphate into the be felt through the skin as hard cords or knobs. Large diffuse fbres are little changed, the hyperplasia affecting the endo tumours may be treated with alternate-day administration and perineurium.

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In diabetes located on the cell membrane of practically every cell arrhythmia research summit purchase 17.5 mg zestoretic overnight delivery, but their increased amount of fat is broken down due to blood pressure food purchase zestoretic us density depends on the cell type: liver and fat cells are very rich wide pulse pressure in young adults buy 17.5mg zestoretic with visa. The subunits carry insulin binding sites blood pressure medication olmetec side effects buy zestoretic 17.5mg with mastercard, while to arteria mesenterica best buy zestoretic fatty acids and triglycerides, but this process the subunits have tyrosine protein kinase activity. Binding of insulin to subunits induces aggregation is reduced in diabetics and acetyl CoA is diverted and internalization of the receptor along with the bound insulin to produce ketone bodies (acetone, acetoacetate, molecules. In turn, a cascade of phosphorylation and the internalized receptor-insulin complex is either dephosphorylation reactions is set into motion which amplifies degraded intracellularly or returned back to the surface from the signal and results in stimulation or inhibition of enzymes where the insulin is released extracellularly. Fate of insulin Insulin is distributed only extra Insulin stimulates glucose transport across cell membrane cellularly. Ultralente (long-acting) and semilente (short-acting) are not separately marketed. During biotransformation the disulfide bonds are reduced—A and B chains are separated. These Types of insulin preparations are further broken down to the constituent amino Regular (soluble) insulin It is a buffered acids. At the concentration Preparations of insulin of the injectable solution, the insulin molecules the older commercial preparations were produced self aggregate to form hexamers around zinc ions. It is generally gel filtration and ion-exchange chromatography injected 1 hour before a meal. The slow onset of action is not appli stable and cause less insulin resistance or injection cable to i. For obtaining retard preparations, insulin is vial and 100 U/ml pen injector cartridge. Their 7:3 ratio mixture is called ‘Lente > 90% diabetics who use insulin are taking human insulin’ and is intermediate-acting. Human insulin is more just sufficient to complex all insulin molecules; water soluble as well as hydrophobic than porcine neither of the two is present in free form and or bovine insulin. It is mostly combined with regular is also modified similarly to produce isophane insulin (70:30 or 50:50) and injected s. Highly purified (monocomponent) pork regular insulin: hypoglycaemic unawareness has not been substantiated. It is unwise to transfer stabilized patients from one to another species insulin Human insulins In the 1980s, the human insu without good reason. Lower lysine at the carboxy terminus B 28 and B 29 incidence of night-time hypoglycaemic episodes positions, it forms very weak hexamers that compared to isophane insulin has been reported. Because of to be injected immediately before or even after acidic pH, it cannot be mixed with any other the meal, so that dose can be altered according insulin preparation; must be injected separately. Using a regimen of 2–3 daily meal to the amino group of lysine at B29 of insulin chain. As time insulin lispro injections, a slightly greater a result, it binds to albumin after s. A pattern of insulin 1c action almost similar to that of insulin glargine is obtained, has been reported. It is reduces the tendency for self-aggregation, and a commonly seen in patients of ‘labile’ diabetes time-action profile similar to insulin lispro is in whom insulin requirement fluctuates unpredic obtained. Hypoglycaemia can occur in any diabetic insulin release pattern after a meal, with the same following inadvertent injection of large dose, by advantages as above. The symptoms can be divided Insulin glulisine: Another rapidly acting insulin analogue into those due to counter-regulatory sympathetic with lysine replacing asparagine at B 23 and glutamic acid stimulation—sweating, anxiety, palpitation, replacing lysine at B 29. Properties and advantages are similar tremor; and those due to deprivation of the brain to insulin lispro. It remains soluble at pH4 symptoms occur before the neuroglucopenic, but of the formulation, but precipitates at neutral pH the warning symptoms of hypoglycaemia differ encountered on s. A depot is created from patient to patient and also depend on the from which monomeric insulin dissociates slowly rate of fall in blood glucose level. Onset of action is delayed, term treatment about 30% patients lose adrenergic but relatively low blood levels of insulin are symptoms. Thus, it is suitable for once ness tends to develop in patients who experience daily injection to provide background insulin frequent episodes of hypoglycaemia. Fasting and interdigestive blood glucose Finally, when blood glucose falls further (to levels are effectively lowered irrespective of time < 40 mg/dl) mental confusion, abnormal of the day when injected or the site of s. Insulin is needed by such in patients who are not able to take sugar orally patients when: and injectable glucose is not available. Lipodystrophy of the subcutaneous fat around the injection site may occur if the same site is injected repeatedly. Allergy this is due to contaminating proteins, and is very rare with human/highly purified insulins. In type oral contraceptives, salbutamol, nifedipine tend 2 patients, insulin dose varies (0. Lithium, high dose aspirin and theophylline basal control by inhibiting hepatic glucose output, may also accentuate hypoglycaemia by enhancing lipolysis and protein breakdown, as well as supply insulin secretion and peripheral glucose utilization. Either multiple normal, avoid symptoms due to hyperglycaemia (2-4) injections daily of long and short acting and glucosuria, prevent short-term complications insulins or a single injection daily of long-acting (infection, ketoacidosis, etc. The advantage is that only two daily injections are required, but the post-lunch glycaemia may not be adequately covered (see Fig. A more intensive regimen termed the ‘basal bolus regimen’ that is now advised needs 3–4 daily injections (see Fig. A long-acting insulin (glargine) is injected once daily either before breakfast or before bed-time for basal Fig. Moreover, patients has established that intensive insulin injected insulin fails to reproduce the normal therapy markedly reduces the occurrence of pattern of increased insulin secretion in response primary diabetic retinopathy, neuropathy, to each meal, and liver is exposed to the same nephropathy and slows progression of these concentration of insulin as other tissues, while complications in those who already have them, normally it receives much higher concentration in comparison to conventional regimens which through portal circulation. Thus, the desirability and practicability of intensive insulin risk of microvascular disease appears to be related therapy has to be determined in individual patients. Symptoms produced are shown within boxes the development of cardinal features of diabetic L/4 hours depending on the volume status. Typically they are renal perfusion is assured change over to N dehydrated, hyperventilating and have impaired saline. The principles of treatment remain mg/dl, 5% glucose in N saline is the most appro the same, irrespective of severity, only the vigour priate fluid because blood glucose falls before with which therapy is instituted is varied. Fall in blood usually normal due to exchange with intracellular glucose level by 10% per hour can be considered stores. Bicarbonate infusion is continued type 2 diabetics the transducer mechanism linking slowly till blood pH rises above 7. Other rare causes are—acromegaly, and treatment of precipitating cause must be Cushing’s syndrome, pheochromocytoma, lipo instituted simultaneously. Hypertension is often Hyperosmolar (nonketotic hypergly accompanied with relative insulin resistance as caemic) coma this usually occurs in elderly part of metabolic syndrome. Its cause is obscure, but appears Acute insulin resistance this form of insulin to be precipitated by the same factors as keto resistance develops rapidly and is usually a short acidosis, especially those resulting in dehydration. These patients are prone the insulin requirement comes back to normal to thrombosis (due to hyperviscosity and sluggish once the condition has been controlled. Despite intensive therapy, mortality in the insulin requirement comes back to normal hyperosmolar coma remains high. Newer insulin delivery devices A number of innova Insulin resistance tions have been made to improve ease and accuracy of insulin administration as well as to achieve tight glycaemia control. Insulin resistance refers to suboptimal response these are: of body tissues, especially liver, skeletal muscle and fat to physiological amounts of insulin. Insulin syringes Prefilled disposible syringes contain specific types or mixtures of regular and modified insulins. Meglitinide/phenylalanine analogues time glycaemia, but was not suitable for round-the-clock Repaglinide, Nateglinide basal effect. Insulin pumps Portable infusion devices connected Exenatide, Liraglutide to a subcutaneously placed cannula—provide ‘continuous 4. Only regular insulin Sitagliptin, Vildagliptin, Saxagliptin, Alogliptin, or a fast acting insulin analogue is used. Amylin analogue mechanism which regulates insulin delivery from a percu Pramlintide taneously refillable reservoir. These have the advantage of providing higher concentrations in Dapagliflozin the portal circulation, which is more physiological. Taking this lead, the first clinically glucose level in normal subjects and in type 2 acceptable sulfonylurea tolbutamide was introduced in 1957. Being more ‘second generation’ sulfonylureas were developed which are potent and clinically superior, only the second 20–100 times more potent. That they do not cause hypoglycaemia phenicol, acute alcohol intake (also synergises in pancreatectomised animals and in type by causing hypoglycaemia). This Adverse effects Incidence of adverse effects is due to increase in number of insulin receptors is quite low (3–7%). It is hypothesized that long-term improvement in carbohydrate lem, may occasionally be severe and rarely fatal. This may be a consequence of their proteins: have low volumes of distribution insulinaemic action. They are primarily metabolized— diarrhoea or constipation, headache and pares may produce active metabolite. Though not a sulfonyl induces insulin release only at high glucose urea, it acts in an analogous manner by binding concentration. Ingested 10 min before meal, injection its plasma t is ~ 3 hours and duration of action it limits postprandial hyperglycaemia in type 2 6–10 hours. There is little effect on fasting blood of these or pioglitazone in poorly controlled type 2 diabetics. Side effects are dizziness, side effect is nausea and vomiting occurring in ~ 50% nausea, flu like symptoms and joint pain. The Ca2+ ions promote fusion of insulin containing intracellular granules with the plasma membrane and exocytotic release of insulin. The HbA1c active inhibitors of this enzyme have been lowering caused by sitagliptin is equivalent to developed as indirectly acting insulin secreta that with metformin. Because reduction is needed in renal impairment, but not of higher risk of lactic acidosis, phenformin was in liver disease. Sitagliptin is well tolerated, side withdrawn and has been banned in India since effects are nausea, loose stools, headache, rashes, 2003. Metformin is reported to action (12–24 hours) despite short plasma t improve lipid profile as well in type 2 diabetics. The major route of elemination is Mechanism of action Biguanides do not by hepatic metabolism; only 20–25% is excreted cause insulin release, but presence of insulin is unchanged in urine. The tolerability of key features of which are: vildagliptin is similar to that of sitagliptin, but 1. This is the major require twice daily dosing; though single daily action responsible for lowering of blood dose suffices in most cases when combined with glucose in diabetics. Interferes with mitochondrial respiratory chain as microvascular complications of diabetes and promotes peripheral glucose utilization • no acceleration of cell exhaustion/ failure through anaerobic glycolysis.

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Doppler ultrasound screening as part of routine antenatal scanning: prediction of pre-eclampsia and intrauterine growth retardation arteria carotis purchase zestoretic 17.5 mg overnight delivery. Doppler velocimetry of the uterine artery as a screening test for gestational hypertension heart attack vol 1 pt 15 buy zestoretic 17.5 mg with mastercard. Uterine artery Doppler flow velocity waveforms in the second trimester for the prediction of preeclampsia and fetal growth retardation blood pressure medication and zoloft discount 17.5mg zestoretic visa. Pregnancy screening by uterine artery Doppler velocimetry – which criterion performs best Prediction of pre-eclampsia hypertension icd 9 generic 17.5mg zestoretic with visa, low birthweight for gestation and prematurity by uterine artery blood flow velocity waveforms analysis in low risk nulliparous women prehypertension erectile dysfunction generic zestoretic 17.5mg. The role of color Doppler imaging of the uterine arteries at 20 weeks’ gestation in stratifying antenatal care. Early Doppler ultrasound screening in prediction of hypertensive disorders of pregnancy. Improved prediction of pre-eclampsia by two-stage screening of uterine arteries using the early diastolic notch and color Doppler imaging. Doppler ultrasound of the uterine arteries: the importance of bilateral notching in the prediction of pre-eclampsia, placental abruption or delivery of a small for-gestational-age baby. One-stage screening for pregnancy complications by color Doppler assessment of the uterine arteries at 23 weeks’ gestation. Randomised controlled trial of Doppler ultrasound screening of placental perfusion during pregnancy. Low-dose aspirin prevents pregnancyinduced hypertension and pre-eclampsia in angiotensin-sensitive primigravidae. The use of aspirin to prevent pregnancy induced hypertension and lower the ratio of thromboxane A2 to prostacyclin in relatively high risk pregnancies. Low-dose aspirin in prevention and treatment of intrauterine growth retardation and pregnancy-induced hypertension. Prevention of preeclampsia with low-dose aspirin in healthy, nulliparous pregnant women. The National Institute of Child Health and Human Development Network of Maternal–Fetal Medicine Units. Doppler ultrasound and aspirin in recognition and prevention of pregnancy-induced hypertension. Prediction of pre-eclampsia by abnormal uterine Doppler ultrasound and modification by aspirin. A randomized controlled trial of aspirin in patients with abnormal uterine artery blood flow. Dietary consumption and plasma concentrations of vitamin E in pregnancies complicated by preeclampsia. Effect of antioxidants on the occurrence of pre-eclampsia in women at increased risk: a randomised trial. A nitric oxide donor improves uterine artery diastolic blood flow in normal early pregnancy and in women at high risk of pre-eclampsia. Effects of nitroglycerin on the uterine and umbilical circulation in severe preeclampsia. The effect of isosorbide dinitrate on uterine artery and umbilical artery flow velocity waveforms at mid-pregnancy. The efficacy and fetal maternal cardiovascular effects of transdermal glyceryl trinitrate in the prophylaxis of pre-eclampsia and its complications: a randomized double-blind placebo-controlled trial. In mild to moderate disease there is a compensatory increase in intramedullary erythropoiesis, and in severe disease there is recruitment of extramedullary erythropoietic sites, such as liver and spleen 2,3. In moderate anemia, the umbilical arterial plasma lactate concentration is increased but this is cleared by a single passage of fetal blood through the placenta and normal umbilical venous levels are maintained 7. In severe anemia, when the oxygen content is less than 2 mmol/l, the placental capacity for lactate clearance is exceeded and the umbilical venous concentration increases exponentially. These data suggest that, in the fetus, systemic metabolic acidosis can be prevented, unless the oxygen content decreases below the critical level of 2 mmol/l 7. When the fetal hemoglobin concentration deficit exceeds 6 g/dl, hydrops fetalis develops 1. This may be the result of extensive infiltration of the liver by erythropoietic tissue, leading to portal hypertension, due to parenchymal compression of portal vessels, and hypoproteinemia, due to impaired protein synthesis 8. Furthermore, at this hemoglobin concentration deficit, the oxygen content decreases below the critical level of 2 mmol/l. However, there is a wide scatter of values around the regression lines describing the associations between the degree of fetal anemia and the data obtained from these indirect methods of assessment. The only accurate method for determining the severity of the disease is blood sampling by cordocentesis and measurement of the fetal hemoglobin concentration. At cordocentesis, a fetal blood sample is first obtained and the hemoglobin concentration is determined. If this is below the normal range, the tip of the needle is kept in the lumen of the umbilical cord vessel and fresh, packed, rhesus-negative blood compatible with that of the mother is infused manually into the fetal circulation through a 10-ml syringe or a transfusion set. At the end of the transfusion, a further fetal blood sample is aspirated to determine the final hemoglobin concentration 13,14. Subsequent transfusions are given at 1–3-weekly intervals until 34–36 weeks, and their timing is based on the findings of non-invasive tests, such as Doppler studies, and the knowledge that, following a fetal blood transfusion, the mean rate of decrease in fetal hemoglobin is approximately 0. Therefore, it is unlikely that fetal anemia alters the uteroplacental circulation. It was suggested that increased impedance to flow in the fetoplacental microcirculation may be due to hypoxemia-mediated capillary endothelial cell damage, or clogging of the placental capillaries by the large fetal erythroblasts. These findings indicate that impedance to flow is not affected by anemic hypoxia and by the alterations of blood constituents, such as hypoproteinemia, or red cell morphology, such as erythroblastemia, that accompany severe anemia 2,3. There was a non-significant increase in both maximal and mean temporal velocities. Furthermore, there was a significant reversal in the E/A ratio in the flow waveforms from the tricuspid valve. In normal fetuses, these two peaks present an ‘M’ shape, whereas in anemic fetuses the E peak is dominant, suggesting that, in fetal anemia, there is an increased pre-load in the right atrium. However, there was no significant relationship between fetal hematocrit and cardiac output. Nevertheless, extremely compromised fetuses demonstrated diminished cardiac function as a terminal finding. Both left and right cardiac outputs were significantly higher for gestation than in 187 normal controls. Furthermore, the E/A ratios of both atrioventricular valves were higher than normal (Figure 1). The total cardiac output was increased by one-third and this was mainly due to an increase of the cardiac output on the right side. The findings of increased fetal cardiac output in anemia are in agreement with the results of animal studies and confirm the prediction, from a mathematical model, that, in fetal anemia, the cardiac output is increased to maintain an adequate oxygen delivery to the tissues 24. Possible mechanisms include, first, decreased blood viscosity leading to increased venous return and cardiac preload and, second, peripheral vasodilatation as a result of a fall in blood oxygen content and therefore reduced cardiac afterload. Figure 1: Flow velocity waveforms across the tricuspid valve in an anemic fetus at 28 weeks of gestation. Since right-to-left cardiac output ratio is normal, there is no evidence of redistribution in cardiac output similar to that described in hypoxemic growth-restricted fetuses. These findings suggest that, in fetal anemia, the changes in fetal cardiac output are mainly due to low blood viscosity. An alternative explanation is that the symmetrical increase in cardiac output is secondary to an increase in catecholamine concentrations in fetal blood induced by anemia 25. Similarly, from the examination of 68 previously untransfused fetuses at 17–37 weeks of gestation, Nicolaides et al. However, separate analysis of non-hydropic and hydropic fetuses demonstrated that in the former group there was a significant positive correlation between increased velocity and fetal anemia, whilst in the latter group there was a significant negative correlation between these two parameters. In an extended series of 95 previously untransfused fetuses undergoing cordocentesis for rhesus disease, there was a significant increase in aortic velocity with the degree of fetal anemia 16. Although, in some hydropic fetuses, aortic velocity was decreased, in the majority of cases the velocity was increased. In an additional series of 212 fetuses that had a transfusion 2–3 weeks previously, the relation between aortic velocity and anemia was weaker. For subsequent transfusions, different formulae had to be used, presumably because of the different rheological properties of adult, rather than fetal, blood in the fetal circulation. There was a significant association between the degree of fetal anemia and the increase in blood velocity. The authors speculated that this increase in common carotid artery velocity reflected increased cardiac output associated with fetal anemia, rather than a chemoreceptormediated redistribution in blood flow, as seen in hypoxemic growth-restricted fetuses 27. In an extended series of 95 previously untransfused fetuses undergoing cordocentesis for rhesus disease, there was a significant association between the increase in mean velocity in the middle cerebral artery with the degree of fetal anemia 16. In an additional series of 212 fetuses that had a transfusion 2–3 weeks previously, the relation between blood velocity and anemia was weaker 16. In a prospective study of 16 fetuses from isoimmunized pregnancies, they found that all the anemic fetuses had peak velocity values above the normal mean for gestation, whereas none of the fetuses with peak velocity below the normal mean was anemic 28. On the basis of these results, they suggested that, in the management of isoimmunized pregnancies, the indication for cordocentesis should be a peak systolic velocity above the normal mean for gestation. These results were confirmed in a multicenter study involving 111 fetuses from isoimmunized pregnancies; all moderately or severely anemic fetuses had increased peak velocity in the middle cerebral artery 29. Furthermore, there was a good correlation between delta peak velocities and delta hematocrits for the first procedure. The deceleration angle between the line describing the average slope during the diastolic phase of the cycle and the vertical axis was measured and expressed in multiples of the median (MoM) for gestational age. A decrease in the deceleration angle was associated with fetal anemia and, at a threshold deceleration angle of < 0. It was concluded that all cases of severe anemia could be identified before the development of hydrops, and, if, in the management of red cell isoimmunization, cordocentesis is only carried out if the deceleration angle is < 0. Figure 2: Blood velocity in the fetal thoracic aorta (left) and middle cerebral artery (right) in red cell isoimmunized pregnancies plotted on the appropriate reference range (mean, 95th and 5th centiles) for gestation. The findings of increased blood velocity in the fetal arteries with anemia (Figure 2 and Figure 3) are compatible with the data from the fetal cardiac Doppler studies. If it is assumed that, in anemia, the cross-sectional area of the fetal descending aorta and middle cerebral arteries does not change, the increased velocity would reflect an increase in both central and peripheral blood flow due to increased cardiac output. The decreased aortic velocity in some hydropic fetuses may be the consequence of cardiac decompensation, presumably due to the associated hypoxia and lactic acidosis and to the impaired venous return due to liver infiltration with hemopoietic tissue 2. Figure 3: Flow velocity waveform in the fetal middle cerebral artery in a severely anemic fetus at 22 weeks (left) and in a normal fetus (right). In fetal anemia, blood velocity is increased Blood velocity in fetal veins Rightmire et al. Although the velocity was higher than in non-anemic controls, there was no significant correlation with fetal hematocrit. In the same study, the intrahepatic umbilical venous velocity was not significantly different from non-anemic controls.

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