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Bergman K: Application and results of whole-body autoradiography in distribution studies of organic solvents discount 100 mg januvia with visa diabetes education classes. Simko V discount januvia 100mg on line diabetic blood sugar chart, Michael S generic januvia 100 mg fast delivery blood glucose blank chart, Katz J, et al: Protective effect of oral acetylcysteine against the hepatorenal toxicity of carbon tetrachloride potentiated by ethyl alcohol. Jonsson F, Bois F, Johanson G: Physiologically based pharmacokinetic modeling of inhalation exposure of humans to dichloromethane during moderate to heavy exercise. Miller L, Pateras V, Friederici H, et al: Acute tubular necrosis after inhalation exposure to methylene chloride. It is used for the production of fluorocarbons, etching glass, and silicone, and as a household rust-removal agent. A related compound, ammonium bifluoride is used in rust removers, commonly found in commercial car washes. Once absorbed, it disassociates and the fluoride anion binds to divalent cations, forming insoluble salts (primarily calcium fluoride, fluorapatite, and magnesium fluoride). Although the initial injury is not always visible, the patients exposed to medium- concentration products often go on to have erythema, blanching, or necrosis of the involved area. The patients may develop full- or partial-thickness injury that includes tissue necrosis and eschar formation [1]. Evaluation and Treatment Laboratory studies are not indicated for small, low-concentration dermal exposures. The most important step in the treatment is decontamination by irrigating the affected area for at least 15 minutes as quickly as possible. Hexafluoride, an irrigating solution developed to bind fluoride, does not appear to offer any improvement over water irrigation [4]. The role of topical therapy following high-concentration exposures is less well defined, but it is recommended [7]. If pain is not relieved by topical therapy, regional intra-arterial or intravenous calcium perfusion should be initiated. Following cannulation, monitor arterial waveform to assure that the catheter remains patent and properly placed within the artery. The blood pressure cuff should be inflated to a pressure of 100 mm Hg above systolic pressure and remain up for 15 to 20 minutes following calcium administration. Irrigation with calcium salts appears to offer no benefit over saline in animal models, and may increase the incidence of ulceration [9]. All patients with persistent symptoms or obvious corneal damage should have immediate evaluation by an ophthalmologist. The patients who are asymptomatic after irrigation should have next-day follow-up with an ophthalmologist. Treatment of these burns with calcium gluconate eyedrops has been suggested, but systematic human studies have not been reported [12]. The patients may present with severe or minimal symptoms and go on to develop complications over time [13]. Although systemic fluoride poisoning may occur [14], the major mechanism of pulmonary injury is acute lung injury. Treatment is supportive, and early airway intervention may be required for the patients with symptoms of upper airway obstruction. There are several uncontrolled reports of good outcomes following treatment with nebulized calcium gluconate solution (2. Although it is commonly recommended to administer calcium or magnesium antacids, animals studies have found that very high doses are required to affect mortality [18,19]. Because successful resuscitation from cardiac arrest following systemic fluoride poisoning is rare, treatment should be started early to prevent cardiac dysrhythmias and arrest. The patients should have continuous cardiac monitoring, reliable vascular access, and frequent measurement of serum calcium and magnesium levels. If the history suggests that there has been a significant exposure, prophylactic calcium should be initiated at a rate of 1 g over 30 minutes [20]. The patients who have normal vital signs and remain stable should have serum calcium levels monitored every 30 minutes for the first 2 to 3 hours. Calcium chloride 1-g boluses should be repeated as needed to maintain the serum calcium in the high normal range. The patients with hypocalcemia, dysrhythmias, or hypotension should receive 2 to 3 g of calcium every 15 minutes, and central venous access should be obtained. Successful treatment of cardiac arrest has generally been associated with administration of large doses (>10 g) of calcium. Intravenous magnesium sulfate 2 to 6 g over 30 minutes followed by a continuous 1- to 4-g infusion has also been suggested. Beyond calcium and magnesium administration, fluoride-poisoned patients require aggressive supportive care. Successful electrical cardioversion for dysrhythmias following calcium and magnesium therapy has been reported [23]. Although this study has obvious limitations, serum alkalinization should be considered in critically ill patients. However, over alkalinization may worsen hypocalcemia; therefore, serum pH should be maintained between 7. Although fluoride is cleared by hemodialysis, the patients with severe poisoning may be too unstable to tolerate dialysis. Hojer J, Personne M, Hulten P, et al: Topical treatments for hydrofluoric acid burns: a blind controlled experimental study. Kono K, Watanabe T, Dote T, et al: Successful treatments of lung injury and skin burn due to hydrofluoric acid exposure. Heard K, Delgado J: Oral decontamination with calcium or magnesium salts does not improve survival following hydrofluoric acid ingestion. Notably, a clinically important proportion of iron overdoses is purposeful, involving adolescents and adults, and resulting in significant morbidity and mortality [3]. The capacity of these systems to cope with an acute overdose is unknown; it likely varies from individual to individual and with the state of iron stores. Incomplete understanding of iron toxicokinetics is primarily responsible for controversies regarding (a) toxic dose; (b) gastrointestinal decontamination; (c) efficacy of intragastric complexation therapies; and (d) the indications, dose, duration, and efficacy of deferoxamine therapy. Its common salts are ferrous gluconate, sulfate, fumarate, and succinate, which are 12%, 20%, 33%, and 35% elemental iron, respectively. Because there is no endogenous mechanism for iron excretion, total body iron is a function of the absorptive process. Absorption occurs in the proximal small bowel, with approximately 10% of the ingested dose absorbed, but with 10-fold variations, depending on iron stores and the amount ingested. The actual mechanism of iron absorption is not well understood, but it is believed to be an active process. The half-life after therapeutic dosing is approximately 6 hours [5], with rapid decline because of tissue distribution. In plasma, iron is bound to transferrin, a specific β1-globulin responsible for iron transport throughout the body.

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In this management strategy 100 mg januvia for sale diabetes hearing loss, cervical cer- rather than the presence or absence of funnelling which clage would be indicated either when cervical length is the principal predictor of spontaneous preterm birth reduces to a fixed cut‐off generic 100 mg januvia fast delivery diabetes yellow toenails, commonly 25mm best januvia 100 mg diabetes definition medical dictionary, or falls (although clearly the presence of funnelling will lead to a below the 10th or 3rd centile for cervical length at that shorter cervical length). In continental Europe it is common It has been suggested that the introduction of routine practice to perform a vaginal assessment of cervical measurement of cervical length at the time of the sec- length at each antenatal consultation, although multi- ond‐trimester anomaly ultrasound scan would enable centre trials have shown that this policy is of no benefit screening of low‐risk populations. It serial measurement of cervical length to assess their risk also appears that there is a relationship between the ges- of preterm labour. It has been widely advocated as an approach for this appears to be associated with a higher risk of pre- the detection of women who would benefit from proges- term delivery. Detection Spiegel’s criteria, by gas–liquid chromatography of vagi- up to 20 weeks is possible because the amniochorion is nal fluid (finding a high ratio of succinate to lactate) or not fully fused with the decidua until that time. Detection on clinical grounds based on a high vaginal pH, a fishy closer to term is a feature of the normal mechanical and odour in a thin homogeneous vaginal discharge and the biochemical events leading to normal term labour. When originally introduced as a commercial test, a risk factor for preterm delivery, it is less clear that treat- fibronectin analysis was principally intended to be used in ing it with antibiotics is beneficial. However, it otics in different regimens and at different times, but it is now being increasingly used to predict risk in women may also reflect the fact that antibiotics may not neces- who are asymptomatic but at risk for other reasons, in sarily result in the re‐establishment of normal bacterial particular cervical shortening. While 34 weeks of less than 10%; this rises to over 50% if the screening of pregnant women who are at high risk for fibronectin concentration is greater than 200 ng/mL. Fetal fibronectin Fetal fibronectin is a glycoprotein variant of the fibronec- Prevention of preterm labour tin family present in amniotic fluid, placenta and the extracellular substance of the decidua. Its synthesis and In primigravid women with no other significant risk fac- release is increased by the mechanical and inflammatory tors for preterm delivery there is currently no effective events which occur prior to the onset of labour. However, it is pos- pole of the uterus associated with the early biochemical sible to identify a group of women in the antenatal period events of parturition. However, it is also an inflammatory who are at risk of preterm delivery based on their past response gene, and therefore concentrations of fibronec- obstetric history, the presence of abnormalities of the tin in vaginal fluid can be considered to also be a marker genital tract, and use of screening tests such as transvagi- of inflammation (which may be pathological or a normal nal ultrasonic measurement of cervical length and detec- part of the onset of labour at term). Various tests, suitable tools to stratify women at risk into different aeti- including assessment of cervical resistance index, hyster- ological groups. Most studies of interventions have ography or insertion of cervical dilators, have been found either had no classification or have selected subgroups of to have no benefit in predicting cervical weakness. Many obstetricians currently use transvaginal ultra- However, the cervix may have its structural integrity sound measurement of cervical length to assess risk of compromised without necessarily being rendered any preterm birth and target intervention by cervical cer- shorter and would nevertheless still benefit from cer- clage in women where there is uncertainty about the clage. If ultrasound‐indicated cervical cer- inflammation within the vagina and cervix, in which case clage is to be used, the appropriate threshold has not yet cerclage might be detrimental. It is possible that some of been universally agreed, although a length below 25 mm the dramatic differences in the effectiveness of interven- is a commonly used cut‐off. The presence of visible fetal tions that are seen in different clinical trials may arise membranes at the time of cervical cerclage is a strong from enrolment of women whose underlying aetiology of prognostic indicator for the risk of preterm delivery. An individual patient data meta‐analysis of four large At present, no prophylactic therapy has been demon- studies of targeted cervical cerclage in women with a strated to be unequivocally beneficial in preventing the short cervix taken from a general obstetric population onset of preterm labour in a high‐risk population. Previously, non‐steroidal anti‐inflamma- therefore generally been concluded that cervical cerclage tory drugs and oral beta‐sympathomimetics have been is of no benefit in a woman with a short cervix but no used. The results of omized trial of cervical cerclage, published in 1993, was this meta‐analysis also stands in stark contrast to a much to assess whether cervical cerclage in women deemed to smaller earlier study which showed a marked benefit of be at increased risk of cervical incompetence prolongs cervical cerclage undertaken by a single senior skilled pregnancy and thereby improves fetal and neonatal out- obstetrician. However, women were randomized only if their of the technical performance of the operation that will obstetrician was uncertain whether to recommend cer- affect the outcome. Therefore cervical cerclage was compared onstrate benefit of cervical cerclage in a large general with a policy of withholding the operation unless it was population of women with short cervix is partly due to considered to be clearly indicated. In this study, the larg- the short cervical length cut‐off, late gestational age at est ever conducted of this question, the overall preterm screening, variable skill and experience of the operators delivery rate was 28% and there were fewer deliveries and technique of the procedure. This case that a population of women at risk of preterm birth difference was reported to be reflected in deliveries char- with a short cervix at the end of the second trimester of acterized by features of cervical incompetence: painless pregnancy represents a mixture of women with genuine cervical dilatation and pre‐labour rupture of the mem- mechanical cervical problems, who would probably ben- branes. The use of cervical cerclage was associated with efit from cervical cerclage, and women whose cervix is a doubling of the risk of puerperal pyrexia. Preterm Labour 399 Whilst the current evidence is that cervical cerclage is the end of the pregnancy. Similarly, leaving large amounts not beneficial in women whose only risk of preterm birth of Mersilene tape in the vagina after cerclage to facilitate is a short cervix in the late second trimester, there is good removal probably increases the risk of adverse outcome. A meta‐analysis of easier, whilst the stitch itself is in an anatomical location four randomized controlled trials of cervical length‐ unexposed to the vaginal microbiota. This group is now often managed in a similar women with multiple pregnancy and a short cervix but way, with a cut‐off cervical length of 25 mm being used to no other risk factors for preterm birth. Although there are no rand- the aetiological differences in the risk of preterm birth omized controlled trials in this group of patients, current between singleton and multiple pregnancy. There are no observational data suggest that this policy reduces their large studies of the role of cerclage in women with twins risk of preterm birth to that of the background popula- who have a past history of second‐trimester pregnancy tion. However, it would be illogical 16 weeks can be used as a screen to discharge women in to deny a woman who had previously benefited from this cohort from further surveillance. Cervical cerclage technique Various different techniques have been described for Emergency ‘rescue’ cerclage cervical cerclage. The operation was originally popular- Rescue cervical cerclage may be performed when a woman ized in the 1950s by Shirodkar as a transvaginal purses- is admitted with silent cervical dilatation and bulging of tring suture placed following bladder mobilization and the membranes into the vagina but without the onset of posterior dissection to allow insertion at the level of the uterine contractions. In the 1960s the simpler McDonald proce- sent with slight vaginal bleeding, a watery vaginal dis- dure of a transvaginal pursestring suture without bladder charge, or vague pelvic or vaginal pain. Some exponents of the literature, mostly composed of case reports and small case McDonald procedure deliberately place the suture mid- series, suggests that rescue cerclage may delay delivery by way along the cervix to reduce the risk of bladder injury a further 5–7 weeks on average compared with expectant and to facilitate removal. It is now clear that the success management/bed rest alone, associated with a twofold of cervical cerclage depends on placing the suture as reduction in the risk of delivery before 34 weeks. In my experience this there are concerns that emergency or rescue cerclage will require dissection of the bladder off the cervix in might convert a second‐trimester pregnancy loss into an more than 50% of cases. Whether antibiotics Mersilene, when used for cervical cerclage and in other are beneficial in such cases has not been established. Some operators who use Mersilene tape completely the central role for prostaglandins and inflammatory bury the suture. Oligohydramnios occurs in Progesterone is probably the most widely used interven- up to 30% of fetuses exposed to indometacin. Currently, is dose dependent and may occur with both short‐term two different progestin preparations are in common use. Discontinuation of therapy the synthetic 17α‐hydroxyprogesterone caproate, which usually results in a rapid return of normal fetal urine out- is chemically similar to testosterone and is not a natural put and resolution of the oligohydramnios. There is a relationship dence suggests that 17α‐hydroxyprogesterone caproate between dose and duration of therapy and gestational is not effective in the group of women whose risk of pre- age. Ductal constriction is seen less commonly below term birth is predicted by a short cervix, nor is it effec- 32 weeks and rarely below 28 weeks. Long‐term indo- tive in women at risk of preterm birth because of multiple metacin therapy, particularly after 32 weeks, is therefore pregnancy. Concentrations of progesterone in shown that administration of indometacin is associated the circulation during normal pregnancy are substan- with a rapid reduction in hourly fetal urine production tially above the Kd for the progesterone receptor. As dis- but that oligohydramnios may develop more slowly and cussed, unlike in other species, in the human progesterone become significant at between 15 and 28 days. The inducible and catalyses the synthesis of prostaglandins at relative binding affinity of 17α‐hydroxyprogesterone the sites of inflammation. In addition, seen in fetuses exposed to indometacin and there have 17α‐hydroxyprogesterone caproate is given as a weekly been isolated case reports of fatal fetal renal failure.

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Once Scr rises above 250 µmol/L there are Antenatal strategy and decision‐making even bigger risks of accelerated loss of renal function cheap 100 mg januvia otc blood sugar zone, and even terminating the pregnancy may not reverse the These women ideally will have had pre‐pregnancy coun- decline (Table 11 purchase januvia 100mg online diabetes medications and diarrhea. Thereafter assessments should usually be performed at Temporary or acute dialysis has been advocated during least every 4 weeks until 28 weeks’ gestation and then pregnancy in the face of overall deterioration in renal every 1–2 weeks depending on the clinical circumstances function (especially when Surea exceeds 20mmol/L and/ [8 buy discount januvia 100mg online managing diabetes journal articles,45]. Dialysis may increase the chance of success- creatinine ratio ideally on a first morning void. Loss of >25% renal function Scr Fetal growth Preterm Pre‐eclampsia Perinatal Pregnancy Persists post End‐stage failure in (µmol/U) restriction (%) delivery (%) (%) deaths (%) (%) partum (%) 1 year (%) ≤125 25 30 22 1 2 – – 125–180 45 70 40 6 40 20 3 ≥180 70 >90 60 12 70 55 35 Estimates are based on literature from 1985 to 2009, with all pregnancies attaining at least 24 weeks’ gestation (Davison & Winfield, unpublished data). Ultrasound may reveal scarred kidneys, of hypertension (and assessment of its severity) and hydronephrosis and function may or may not be normal. If anaemia is persistent and resistant develop lupus nephritis, this is one of the commoner to iron, recombinant human erythropoietin can be forms of renal disease seen in pregnant women. Proteinuria increases the risk of women all of whom had prior or active lupus nephritis thrombosis and in the face of significant proteinuria and had undergone pre‐pregnancy counselling. The clinical watchpoints Importantly, the use of the antimalarial hydroxychloro- associated with specific renal diseases are summa- quine appeared to significantly reduce the probability of rized in Table 11. Furthermore, there is depletion or electrolyte imbalance (occasionally precipi- some disagreement about whether pregnancy adversely tated by inadvertent diuretic therapy), should be sought. Failure to detect a reversible cause of a significant actually similar to that of women with mild impairment decrement may be an indication for early delivery. Renal disease Clinical watchpoints Chronic glomerulonephritis In the absence of hypertension and abnormal renal function, most of these women will have normal and focal segmental pregnancies though probably have a higher risk of late hypertension and pre‐eclampsia. Most note good outcome when renal function is preserved Chronic pyelonephritis Bacteriuria in pregnancy, recurrent urinary tract infections (often requiring prophylactic antibiotics) (infectious tubulointerstitial and frequent hypertension disease) Reflux nephropathy Some have emphasized risks of sudden escalating hypertension and worsening of renal function. Consensus now is that results are satisfactory when pre‐pregnancy function is only mildly affected and hypertension is absent. Vigilance for urinary tract infections is necessary Urolithiasis Ureteral dilatation and stasis do not seem to affect natural history, but infections can be more frequent. Stents have been successfully placed and sonograpically controlled ureterostomy has been performed during gestation Polycystic kidney disease Outcomes largely predicted by baseline function and hypertension. Women should be advised to have their pregnancies before they have lost function Diabetic nephropathy Proteinuria is likely to increase significantly during pregnancy and if nephropathy is advanced, salt and water retention may predominate. Most women with diabetes do not have overt nephropathy during their childbearing years; however, this is becoming more common as women have children later in life and the rates of type 2 diabetes in younger women increase. Increased frequency of infections, oedema or pre‐eclampsia Human immunodeficiency Renal component can be nephrotic syndrome or severe impairment. If the mother has anti‐Ro antibodies she should be offered fetal echocardiography at 18/40 to look for early signs of congenital heart block Systemic vasculitis If in remission will have little impact on pregnancy. However, flares can occur and if severe may (granulomatous or mandate early termination of pregnancy to allow adequate treatment of aggressive renal disease. Rare microscopic polyangiitis) Scleroderma If onset during pregnancy, there can be rapid overall deterioration. Reactivation of quiescent scleroderma can occur during pregnancy and after delivery Previous urologic surgery Depending on original reason for surgery, there may be other malformations of the urogenital tract. Urinary tract infection is common during pregnancy and renal function may undergo reversible decrease. No significant obstructive problem, but caesarean section might be necessary for abnormal presentation or to avoid disruption of the continence mechanism if artificial sphincters or neourethras are present After nephrectomy, solitary Pregnancy is well tolerated. The use of acute dialysis nosis cannot be made with certainty on clinical grounds has been mentioned earlier. Most of the specific risks hypertension (diastolic blood pressure <95mmHg in 136 Maternal Medicine the second trimester or <100mmHg in the third) was considered to rarely justify the risks [5,9]. However, there not previously necessarily considered mandatory during are now case series reporting safety in selected cases in normal pregnancy, but many would treat women with early pregnancy. However, ‘blind’ treat- pregnant women with renal disease, particularly those ment with steroids or other immunosuppressants is not with proteinuric renal disease, the target blood pressure without risk and having a firm diagnosis is very helpful. In reality, biopsy during pregnancy blockers, labetalol and hydralazine are safe in pregnancy. When renal biopsy is undertaken immediately after recommended beyond the early first trimester. In those women with heavy proteinuria and pro- gressive renal decline, the benefit of continued renal Long‐term effects of pregnancy in women protection probably outweighs the low risk of early first with renal disease trimester exposure. In those women we advise cessation as soon as pregnant in order to avoid months pre‐preg- Readers are referred to earlier sections for advice regarding nancy with no renal protection. An important Serial evaluation of fetal well‐being, with regular assess- factor in long‐term prognosis could be the sclerotic ment of fetal growth, amniotic fluid and Doppler, is effect that prolonged gestational renal vasodilatation essential. In the absence of fetal or maternal deteriora- might have in the residual (intact) glomeruli of the kid- tion delivery should be at or near term. The situation may be worse in a do arise, the judicious moment for intervention might be single diseased kidney, where more sclerosis has usually determined by fetal status (see Chapter 28). Although of gestational age, most babies weighing more than the evidence in healthy women and those with mild renal 1500 g survive better in a special care nursery than a hos- disease argues against hyperfiltration‐induced damage tile intrauterine environment. Planned preterm delivery in pregnancy, there is little doubt that in some women may be necessary if there is impending intrauterine with moderate, and certainly severe, dysfunction there fetal death, if renal function deteriorates substantially, can be unpredicted, accelerated and irreversible renal if uncontrollable hypertension supervenes, or if pre-eclamp- decline in pregnancy or immediately afterwards. It seems that pre‐eclampsia is Renal Disease 137 not a risk factor (‘marker’ is a better term) for progression include time on dialysis of less than 5 years, age under (see Chapter 7) but can lead to a stepwise decrease in 35 years, residual urine production and absence of or renal function in those with underlying renal disease. Pregnant women Patients on dialysis on dialysis should be offered increased hours of dialy- sis, aiming for at least 24 hours per week. All such preg- Dialysis and the prospects for pregnancy nancies should be considered high risk, with increased and afterwards potential for volume overload, threat of preterm labour, polyhydramnios (40–70%; directly related to adequacy Despite reduced libido and relative infertility, women of dialysis), major exacerbations of hypertension and/or on long‐term dialysis do conceive and must therefore superimposed pre‐eclampsia (50–80%) and rarely, for- use contraception if they wish to avoid pregnancy tunately, placental abruption. Although conception is not common (an incidence of 1 in 200 patients has been quoted), its true frequency is unknown because many pregnancies Antenatal strategy and decision‐making in dialysis patients probably end in early spontaneous abortion. The high therapeutic abortion rate in this If women on dialysis become pregnant, they may present for care in advanced pregnancy because it was not sus- group of patients (which has decreased from 40% in the 1990s to under 15% today) still suggests that those pected by either the patient or her doctors. Irregular menstruation is common and missed periods are usually who become pregnant do so inadvertently, probably ignored. Urine pregnancy tests are unreliable (even if because they are unaware that pregnancy is possible. Recent data on improved fertility, likely due to normal- there is any urine available). Thus ultrasound evaluation ization of the hypothalamic–pituitary–gonadal axis, is needed to confirm and date pregnancy. A lower Surea is definitely associated with higher ● Incidence of conception in chronic haemo dialysis birthweight and gestational age at delivery. Use a dialysate with a higher potassium, ● Frequency of dialysis must be increased as soon lower calcium and lower bicarbonate. There is now as pregnancy is diagnosed and management of good evidence that nocturnal dialysis (up to 36 hours anaemia, nutritional issues and hypertension is very per week) is associated with much better outcomes. Increased dialysis hours, however minimal, should make control of weight gain and dietary management easier.

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