Bernhard Meier, MD

• Professor of Medicine
• Chairman, Department of Cardiology
• University Hospital Bern
• Bern, Switzerland

As mentioned earlier symptoms of anxiety cheap 10mg atarax with amex, a smaller anxiety untreated purchase atarax pills in toronto, manually delivered volume is typically used when the neonate is started on dialysis and is progressively increased to the limits noted above anxiety upon waking buy atarax 25 mg on line. In the chronic setting can anxiety symptoms kill you cheap atarax 25mg on line, an initial empiric dwell time of 1 hour is often used in infants anxiety symptoms anger buy atarax 25 mg without prescription, although consideration has to be made for clearance of larger molecules that would be favored by longer dwell times anxiety jealousy cheap 25 mg atarax free shipping. Phosphate removal is less of a consideration in these patients compared with older children, as neonates and infants characteristically receive formula with a low phosphorus content or breast milk and may actually require supplemental phosphorus. This poor efficacy was due to enhanced absorption of icodextrin across the peritoneal membrane with half of the patients showing substantial absorption, even when dwell times were reduced from 10 to 6 hours. Parameters that should be taken into consideration include linear growth and weight gain, increase in head circumference, and neurocognitive/psychomotor development. An additional qualitative target of dialysis adequacy in the neonate and infant are the avoidance of hypovolemia and sodium depletion. In order to avoid the negative consequences of protein depletion, current guidelines recommend a dietary protein intake of at least 1. Infectious complications including exit-site infections and peritonitis also occur at a higher rate in neonates and infants. Data from four separate international registries show a slightly lower survival rate for those patients who initiate dialysis within the first month of life, with 2- and 5-year survival rates of 81% and 76%, respectively. Wood et al clearly showed that comorbidities such as anuria and pulmonary hypoplasia were associated with the greatest risk of mortality in infants undergoing dialysis. Conclusion the last two decades have witnessed tremendous advances in the care of the neonate/ infant requiring renal replacement therapy. There have been notable improvements in patient survival, although complications remain high, especially in those infants with comorbidities. All of these issues highlight the need for a multifaceted approach to care to minimize or prevent complications and in turn promote growth, development, and readiness for transplant. Use of the multipurpose drainage catheter for the provision of acute peritoneal dialysis in infants and children. Early initiation of peritoneal dialysis in neonates and infants with acute kidney injury following cardiac surgery is associated with a significant decrease in mortality. This single-center retrospective cohort study of 146 neonates and infants requiring peritoneal dialysis following cardiac surgery found that early dialysis was associated with a significant decrease in mortality in neonates and infants with acute kidney injury. Pulmonary function variation in ventilator dependent critically ill infants on peritoneal dialysis. Outcome of patients initiating chronic peritoneal dialysis during the first year of life. Tenckhoff catheters prove superior to cook catheters in pediatric acute peritoneal dialysis. Is peritoneal dialysis adequate for hypercatabolic acute renal failure in developing countries Icodextrin re-absorption varies with age in children on automated peritoneal dialysis. Clinical experience with icodextrin in children: ultrafiltration profiles and metabolism. Impact of fill volume changes on peritoneal dialysis tolerance and effectiveness in children. Use of intraperitoneal pressure, ultrafiltration and purification dwell times for individual peritoneal dialysis prescription in children. Peritoneal dialysis prescription in children: bedside principles for optimal practice. Low-volume peritoneal dialysis in 116 neonatal and paediatric critical care patients. Consenus Guidelines for the Prevention and Treatment of Catheter-related Infections and Peritonitis in Pediatric Patients Receiveing Peritoneal Dialysis: 2012 Update. Guidelines by an Ad Hoc European Committee for Elective Chronic Peritoneal Dialysis in Pediatric Patients. In urea cycle defects or in organic acidemias, these symptoms are mainly due to excessive hyperammonemia, which may cause irreversible neuronal damage. During the past three decades, the prognosis of these previously lethal disorders has been considerably improved by the introduction of several therapeutic principles. The de novo synthesis of toxic metabolites can be suppressed by a high caloric supply inducing a state of anabolism and reduced proteolysis. In hyperammonemic disorders, new medications that utilize alternative metabolic pathways to reduce neurologic effects. These include sodium benzoate, sodium phenylbutyrate, carbaglutamate, and various vitamins and cofactors. Finally and most importantly, the accumulation of the small, water-soluble neurotoxic metabolites can be rapidly reversed by dialytic removal. Because the brain damage induced by neurotoxic metabolites is directly correlated with the duration of exposure to the neurotoxic metabolites, neonatal metabolic crises are considered emergency dialysis indications requiring use of the most readily available and effective dialysis modality. Because technological advances have improved the suitability of extracorporeal blood purification techniques for neonates, they are now the therapy of choice in appropriately equipped and experienced centers. It offers the advantage of extracorporeal dialysis, as well as additional advantages of smaller venous access down to 4 Fr, without sacrificing clearance or causing hemolysis. In addition, the accurate flow monitoring provides benefits to patient safety, though large-scale randomized controlled trials are not available to demonstrate advantages in survival neurological sequelae. However, repeated sessions are frequently required because of residual or rebound hyperammonemia. Extracorporeal Blood Purification Dialysis Equipment Catheter the choice of catheter has to draw a balance between the aim of achieving an adequate blood flow and the risks of catheter insertion in a newborn. Although umbilical catheters are unsuitable for dialysis because of their high flow resistance, 6. However, the efficacy of the system for ammonia clearance has not yet been reported. Dialyzer Polysulfone dialyzers are preferred because of their superior biocompatibility and lower anticoagulation requirements. The surface of the dialyzer membrane should approximately match the body surface area of the patient. Another disadvantage is that an incorrect blood flow rate is displayed when small-volume neonatal tubes are used. Devices designed for continuous renal replacement treatment are better suited for acute dialysis in children. When considering the choice of a device in a neonate, the extracorporeal volume and accurate flow controls are important. Given the small blood volume of small neonates, volumes larger than 10% estimated blood volume (80 mL/kg) require circuit priming with blood. With very low flow rates, the percentage of error of a few milliliters per minute can be disastrous and cause unforeseen fluid overloading or shock. In order to set it up, a separate central venous line is required for calcium substitution. Care must be taken not to replace the calcium via the postfilter circuit as this can lead to circuit clotting. Care must be noted that adjustments will more likely be needed in the neonatal circuits because of the increased circuit citrate required consequent to blood priming and also immaturity of the liver function due to the age and the metabolic disease. The dialysate flow rate required to achieve maximal clearance is determined by the blood flow rate achieved. As a rule of thumb, extraction of these metabolites is maximal when dialysate flow exceeds blood flow by at least a factor of two. The dialysis fluid should contain glucose and potassium at plasma concentrations and serum phosphorus levels should be monitored closely. The major complications to consider when dialyzing neonates or small infants with metabolic crises are clotting of the extracorporeal system and hemodynamic instability, each of which can cause treatment interruptions and hence hazardous delays in the removal of toxic metabolites. Hypotensive episodes and osmotic dysequilibrium occur less frequently than in neonates and infants dialyzed for renal failure, because dialysis is usually isovolemic and the accumulated metabolites are osmotically less active than the urea accumulated in uremia. However, hemodynamic instability is common in patients with prolonged duration of hyperammonemia because of urea cycle disorders but can be minimized by prefilling the system with blood and using appropriate extracorporeal tubing and dialyzer membranes with a total fill volume as small as 35 mL. Whether this novel therapeutic concept will result in reduced dialysis need and improved outcomes remains to be proven. Peritoneal Dialysis Because of the lower toxin clearance, peritoneal dialysis is generally not recommended and should only be considered when extracorporeal techniques are prohibited by vital sign contraindications or technical limitations. Catheter Stylet catheters can be placed immediately but bear a high risk for the subsequent development of leakage or outflow obstruction. Catheter leakage requires a reduction of dwell volumes or catheter replacement, and outflow obstruction may result in an increased intraperitoneal residual volume, both causing a further decrease of the peritoneal clearance. Dialysis Prescription Prescription of fill volumes must be balanced between maximizing toxin removal and adverse effects of increased intraperitoneal pressure (respiratory problems, catheter leakage). Feasibility of adjunct therapeutic hypothermia treatment for hyperammonemia and encephalopathy due to urea cycle disorders and organic acidemias. Extracorporeal dialysis in neonatal hyperammonemia: modalities and prognostic indicators. Continuous flow peritoneal dialysis: first experience in children with acute renal failure. Neonatal hemodialysis: Effective therapy for the encephalopathy of inborn errors of metabolism. Efficacy and safety of intermittent hemodialysis in infants and young children with inborn errors of metabolism. We conclude the chapter by providing suggestions that might help achieve better understanding of this significant complication of kidney disease in children. Because much cognitive development and learning occur during childhood and early adolescence, it is critical to investigate conditions that have a negative impact on these functions. In patients on dialysis, presence of hypertension, anemia, suboptimal nutrition, microvascular disease, and seizures are known to negatively affect neurocognitive performance. These include lower intellectual functioning, executive functioning deficits, memory and attention problems, and associated learning difficulties and developmental difficulties. In particular, infancy is a vulnerable period associated with rapid development and growth of the nervous system and, hence, infants on dialysis therapy are the ones with greatest risk for disruption of their development, perhaps resulting in delay or impairment. Earlier studies from the 1970s and 1980s reported neurotoxicity and associated neurocognitive effects such as seizures, encephalopathy, and speech delays with use of aluminum-containing phosphate binders in children on dialysis. By 1990, treatment regimen was modified for dialysis patients in order to eliminate aluminum and aluminum-containing medications from the standard practice in dialysis. The peritoneal membrane acts as the semipermeable membrane across which diffusion and ultrafiltration occur, which, in turn, facilitate the removal of substances from the blood. Ultrafiltration and fluid removal are both achieved via an osmotic pressure generated by various concentrations of dextrose or icodextrin. General developmental delay was noted in two of eight (25%) young children, and hyperactivity was described in 50% of the patients. Findings in Older Children and Adolescents In older children receiving dialysis, a similar pattern of findings has emerged. No significant difference was noted in mean developmental (mental and psychomotor) scores between patients undergoing dialysis and those not undergoing dialysis at the time of testing (mean = 78. However, significant improvements in cognitive and psychomotor functions were noted following successful renal transplantation. Significant individual improvement in occipitao frontal head circumference standard deviation score also was noted in 24 children after renal transplantation (p <.

Captopril contains a sulfhydryl group anxiety 5 year old buy atarax 10 mg online, which increases the frequency of some side effects anxiety relief techniques order atarax cheap. Neutropenia and agranulocytosis may appear after 3 to 12 weeks of therapy anxiety university california trusted 10 mg atarax, particularly in patients with autoimmune collagen vascular diseases anxiety burning sensation atarax 25mg cheap. Symptoms may range from mild edema of the mucosa of the eyes to nausea and vomiting anxiety 247 purchase atarax overnight, bronchospasm anxiety 5 months postpartum atarax 25 mg fast delivery, hypotension, and angioedema. It is 47% to 51% bound in human plasma and has a substantial extravascular volume of distribution. Excretion occurs almost entirely by the biliary route, primarily as unchanged drug, with less than 1% renal excretion. Side Effects the side effects of aliskiren include angioedema; periorbital edema; and edema of the face, hands, or whole body, which occasionally required discontinuation. There is also an association with abdominal pain, reflux, dyspepsia, and diarrhea, which are dose dependent. Aliskiren should be avoided during pregnancy because of the concern for fetal and neonatal morbidity and mortality. There are also small risks of hyperkalemia, elevated creatine kinase levels, increase in uric acid levels, and tonic-clonic seizures. Mineralocorticoid Receptor Antagonists Spironolactone has been successfully used in dialysis patients to control refractory hypertension and to prevent cardiovascular events. Beta-blocking agents reduce morbidity and mortality in patients with ischemic heart disease and heart failure, and in patients with heart failure, they reduce the incidence of atrial fibrillation, ventricular arrhythmias, and sudden death. An open-label study showed that atenolol-based antihypertensive therapy may be superior to lisinopril-based therapy in preventing cardiovascular morbidity and allcause hospitalizations in dialysis patients with hypertension and left ventricular hypertrophy. Thus, the antihypertensive action of beta-blockers may be partly due to reduction of cardiac output. Nebivolol, a beta1-blocker that also stimulates nitric oxide production, exerts vasodilatory actions that are unique for this class of agents. Moreover, the hypotensive action of beta-blockers reaches its peak after several days of treatment, but the decrease in plasma renin occurs more rapidly. A large number of -adrenergic blocking agents with differing pharmacodynamic and pharmacokinetic properties are available (see Table 53. For example, propranolol, acebutolol, and metoprolol are well absorbed from the small intestine, but because of extensive first-pass metabolism by the liver, only 30% to 50% of these drugs reaches the systemic circulation. The concomitant use of drugs that affect hepatic blood flow may further reduce the bioavailability of these beta-blockers. By contrast, atenolol, acebutolol, and nadolol are agents with low degrees of lipid solubility that are primarily renally excreted. Accumulation of beta-blockers with low lipid solubility may result in excessive bradycardia. Consequently, the dose of most liposoluble agents do not need to be adjusted in patients with renal failure, but the dose of agents with low lipid solubility should be adjusted. An observational study by Weir et al revealed a possible association between the use of highly dialyzable beta-blockers. Cardioselectivity the second important characteristic distinguishing these agents is cardioselectivity, which is of limited clinical relevance with respect to the antihypertensive efficacy but is of considerable importance with respect to side effects. Cardioselective betablockers are less likely to cause bronchospasm, Raynaud phenomenon, or disturbances of lipid and carbohydrate metabolism. The 1-selective beta-blockers include atenolol, metoprolol, bisoprolol, acebutolol, and nebivolol. Hemodynamically, this results not only in decreased peripheral vascular resistance but also in less pronounced reductions in heart rate, cardiac output, and plasma renin secretion. Some beta-blockers, such as labetalol and carvedilol, have combined and antagonistic properties. The ratio of - to -blocking activity is between 1: 3 618 the Challenges of Blood Pressure Control in Dialysis Patients and 1: 7. Acutely, the drug may cause slight reflex tachycardia, but chronic administration may actually decrease heart rate. The intravenous form has been used with some success in hypertensive emergencies even though its efficacy is not as predictable and immediate as that of sodium nitroprusside. The most common side effect is orthostatic hypotension, which is related to the -blocking properties. Labetalol is less likely to cause bronchospasm and has no deleterious effects on serum lipids. Occasionally, it can increase the titer of antinuclear and antimitochondrial antibodies. Similarly, administration of cyclooxygenase inhibitors should be avoided because they may antagonize the antihypertensive effect of beta-blockers. Because beta-blockers increase the number of receptor sites on vascular smooth muscle cells, caution must be exercised when these drugs are to be withdrawn because of the possibility of coronary artery spasm or arrhythmias. Centrally Acting Antiadrenergic Agents -Methyldopa the antihypertensive action of -methyldopa is primarily caused by activation of 2-adrenergic receptors in the brainstem and partially by biotransformation into a the Challenges of Blood Pressure Control in Dialysis Patients 619 false neurotransmitter. Part of the antihypertensive effect of clonidine may be mediated by central I1-imidazoline receptors localized in the rostral ventrolateral medulla. The drug is readily absorbed from the intestine and reaches peak plasma levels within 1 hour. The antihypertensive action appears within 30 minutes, and it peaks within 2 to 4 hours. In addition, hypertensive crisis may occur when the drug is discontinued abruptly. This rebound effect is more frequent and severe when the drug is given in dosages exceeding 0. In this instance, the surge of catecholamines that occurs after withdrawal of the drug binds preferentially to unoccupied -receptors rather than to the drug-bound -receptors, resulting in greater vasoconstriction and more severe hypertension. The transdermal form of delivery can cause skin rash at the site of adherence of the patch. Guanabenz and Guanfacine Guanabenz and guanfacine are 2-agonists similar in function to clonidine. The liver mainly excretes guanabenz, and no dose adjustment is necessary in patients with 620 the Challenges of Blood Pressure Control in Dialysis Patients renal failure. Guanfacine has a more prolonged duration of action than clonidine and may be given twice daily. Peripherally Acting 1-Adrenergic Receptor Blocking Agents Prazosin Prazosin is a quinazoline derivative with a dual mechanism of antihypertensive activity: direct smooth muscle relaxant effects and peripheral 1-adrenergic receptor inhibition. Prazosin does not significantly affect presynaptic 2 receptors and thus does not stimulate the heart rate or plasma renin release. Epinephrine and norepinephrine occupy the presynaptic inhibitory 2 receptors, thereby reducing further release of catecholamines from the sympathetic end-terminals. The efficacy of the drug is similar to that of hydralazine, but prazosin is less likely to cause tolerance. The most troublesome side effect of prazosin is the "first-dose phenomenon," which is significant orthostatic hypotension occurring after administration of the first dose. Other side effects include syncope, dizziness, diarrhea, and nausea in addition to a postural hypotension that is independent of the first-dose effect. Terazosin Terazosin is a congener of prazosin with similar 1-adrenergic inhibition. The oral absorption of this drug is more gradual than that of prazosin, resulting in higher blood levels 8, 12, and 16 hours after administration of an oral dose. The half-life of terazosin is approximately 12 hours and is not altered by renal failure, making it possible to administer the drug once daily. Doxazosin Similar to terazosin, doxazosin is a quinazoline derivative with a long half-life, making it suitable for once-a-day administration. The Challenges of Blood Pressure Control in Dialysis Patients 621 Urapidil Urapidil, a derivative of arylpiperazine uracil, is a peripheral 1-adrenergic receptorblocking agent with an additional central component that is different from that of clonidine as it does not involve stimulation of central 2-adrenoceptors. The oral bioavailability is variable, and the urinary excretion of the unchanged drug is 50%. The antihypertensive effects of the metabolites are one 10th that of the intact compound. Renal failure results in the accumulation of the drug and its metabolites, so the dosage must be reduced accordingly. Guanethidine has virtually no role in the management of patients with renal failure because of the high incidence of severe side effects. Orthostatic hypotension, impotence, and retardation of ejaculation are extremely common. Diarrhea, bradycardia, and nasal stuffiness are also common and are due to uninhibited parasympathetic activity. Guanadrel Guanadrel is an analog of guanethidine with a shorter half-life and a shorter duration of action. Direct Vasodilators Vasodilators exert their antihypertensive effect by a direct action on vascular smooth muscle cells. Relaxation of vascular smooth muscle cells occurs when there is reduced phosphorylation of myosin light chains. Calcium channel antagonists primarily inhibit the voltage-dependent calcium channels, leading to less movement of calcium across vascular smooth muscle and cardiac cells, inhibition of myosin light chain phosphorylation, and subsequent relaxation of smooth muscle cells. The dihydropyridines include nifedipine, felodipine, amlodipine, nitrendipine, nimodipine, isradipine, nisoldipine, and nilvadipine. The nondihydropyridine agents include diltiazem, which is structurally related to the benzodiazepines, and verapamil, which is structurally similar to papaverine. Cilnidipine also attenuated the decrease in renal blood flow and in urinary sodium excretion caused by renal nerve stimulation in anesthetized dogs. The dihydropyridines have a significant hepatic first-pass effect, and their bioavailability is between 6% and 30%. Urinary excretion is less than 1% of felodipine, nisoldipine, nitrendipine, and nimodipine and approximately 10% in the other dihydropyridines. Nicardipine and nimodipine appear to have more selective action on the cerebral circulation and to be useful in the setting of cerebrovascular accidents. Some studies have shown that these drugs may prevent ischemia-induced mitochondrial overload of calcium during reperfusion. As a result of peripheral vasodilation, dihydropyridines may reduce the incidence of Raynaud phenomena. The dihydropyridines are more likely to cause flushing, headache, tachycardia, ankle edema, and nausea. Verapamil is more likely to cause conduction disturbances, bradycardia, and the Challenges of Blood Pressure Control in Dialysis Patients 623 constipation. Nifedipine capsules should not be used for the management of hypertensive crisis or severe hypertension because of increased risk of myocardial infarction and stroke. The practice of using this agent in patients with dialysis-induced hypertension has been abandoned. Calcium channel blockers may increase blood levels of 25-hydroxy vitamin D but not the levels of 1,25-dihydroxy vitamin D. Sodium Nitroprusside Sodium nitroprusside is the most effective intravenous vasodilator available. It has the advantage of being both an arteriolar and venous vasodilator, thus reducing both preload and afterload of the heart so that no increase in cardiac output occurs. The antihypertensive activity ensues immediately, and it also terminates rapidly because the drug is quickly biotransformed into inactive metabolites such as thiocyanate and cyanogen. In patients with renal failure, these toxic metabolites can accumulate and cause delirium, seizures, coma, and hypothyroidism. To prevent these toxic effects, the drug should not be administered for more than 2 to 3 days. If more prolonged administration is required, serum thiocyanate and cyanate levels should be monitored closely, and, if needed, dialysis should be instituted to remove the toxic metabolites. Hydroxocobalamin may prevent cyanide transfer from red blood cells and plasma into tissue, thereby preventing cyanide toxicity from large intravenous doses of the drug. The increase in compliance is mainly due to an increase in arterial diameter, but distensibility and pulse-wave velocity do not change. Diazoxide Diazoxide is another vasodilator suitable for intravenous administration in hypertensive emergencies. Diazoxide is a benzothiadiazine derivative, chemically related to the thiazide diuretics. This action results in decreased afterload with resultant increase in venous return, heart rate, and cardiac output. The drug has a rapid onset of action, and the antihypertensive activity may last from 4 to 24 hours. It has been customary to administer 100 to 150 mg of the drug by rapid intravenous bolus injection to achieve high concentrations of the unbound form at the level of the vascular smooth 624 the Challenges of Blood Pressure Control in Dialysis Patients muscle cells, thus yielding a more rapid and effective antihypertensive response. The most common adverse reactions are sodium and water retention, hyperglycemia, electrocardiographic ischemic changes, angina pectoris, hypotension, nausea and vomiting, and hyperuricemia. Hydralazine Hydralazine, like diazoxide, is predominantly an arteriolar vasodilator.

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Kt/V was at essence part of the emerging ureacentric tradition but broke from the existing paradigm in two key respects anxiety symptoms mimic ms cheap 25 mg atarax with visa. The first distinction was that Kt/V attempted to balance urea removal (the numerator anxiety symptoms similar to heart attack discount 25 mg atarax free shipping, K*t) to physiologic need (the denominator anxiety 9 months postpartum discount atarax 25mg with visa, V) anxiety symptoms valium treats purchase atarax 25 mg mastercard. The second distinction is subtle but nonetheless important: It changed the paradigm by which urea was considered from how much is there in the body to how much is removed during dialysis anxiety symptoms not going away 10mg atarax with visa. In typical mid1980s circumstances anxiety symptoms in men purchase atarax no prescription, this distinction would have been academic: Technologies were reasonably homogeneous, and nearly all hemodialysis patients were dialyzed according to a thrice-weekly hemodialysis schedule. However, as we shall see later, interim changes in dialyzer efficiency and greater use of quotidian hemodialysis regimens have necessitated subsequent adaptations. This name derives from the conceptual kinetic model through which the equations were derived, which are largely analogous to first-order elimination kinetics. Within the original paper, and more so subsequently in later papers, there are a number of mathematic equations by which 276 TheDialysisPrescription spKt/V can be calculated. Perhaps the most popular of these is the Daugirdas formula, which states, spKt V = - log(R - 0. The use of closed-form equations to calculate Kt/V has largely been supplanted by iterative computer algorithms-the most popular of which is termed ureakinetic modeling-the Daugirdas equation is nonetheless revealing as to the constituent components of spKt/V. The first term in the equation (quantitatively the most important) describes the amount of urea that is removed from the start to the end of a dialysis treatment; this is an alternative mathematical formulation of the urea reduction ratio, which will be discussed in the next section. The second term in the equation corrects for urea generation during the dialysis treatment itself. To understand this term, consider that the typical thrice-weekly in-center hemodialysis patient spends approximately 7% of the time (12 of 168 hours) on dialysis; therefore one would anticipate that at least 7% of urea is generated during dialysis itself (perhaps more if one considers the catabolic nature of hemodialysis). The effect of this is that the change in body urea content will underestimate the amount of urea being removed, an effect for which this term attempts to compensate. The third term in the equation accounts for urea that is removed convectively through ultrafiltration. Because urea is freely permeable across the dialysis membrane, it exists in essentially equal concentration in the blood as in ultrafiltrate. Therefore, although urea is removed in the process of ultrafiltration, this is not otherwise reflected in blood urea concentration. The latter two terms are necessary because the prevailing paradigm is to measure urea removal on the patient-side. Both terms are similar in that they upwardly adjust spKt/V for factors not reflected directly in blood urea concentration change. Nonetheless, the two are largely considered interchangeable, and both are endorsed by guideline committees as valid markers of dialysis adequacy. Recall that success and failure were defined in that study as hospitalization or terminal withdrawal from dialysis. Beginning in the early 1990s, there was a proliferation of observational studies that looked at the association between achieved urea removal and mortality. At the time these initial studies were conducted, comparatively few patients had spKt/V much greater than 1. In parallel, technological changes to dialyzers greatly improved the efficiency of urea removal. By the mid-1990s, it had become tenable to achieve greater urea removal in the context of thrice weekly in center hemodialysis than had previously been the case. Patients were randomized to higher versus lower Kt/V; technically, Kt/V was defined based on equilibrated Kt/V (which will be discussed below) but was functionally equivalent to spKt/V of 1. Equilibrated Kt/V Use of urea as the currency for small-molecular-weight dialytic clearance is based on the notion that urea is freely permeable across membranes. Urea is small (molecular weight 60 Da) and uncharged, which are ideal characteristics for promoting passive diffusion across lipid bilayers. Urea present in less perfused tissues has less access to the central circulation and thereby is less available for dialytic removal. Moreover, there are vascular beds for which perfusion decreases during dialysis (in response to circulatory stimuli and the neuroendocrine milieu). Together, these regions form a reservoir for urea and other otherwise-freely transferrable solutes. In other words, small molecule clearance from these regions is kinetically limited. These levels reflect well the behavior of urea in the blood at other highly perfused tissues; however, they do not reflect 278 TheDialysisPrescription the behavior of urea in more inaccessible tissues. In fact, if one serially samples blood urea after the end of dialysis, one observes a "rebound" in blood urea levels that represents the reequilibration of urea across body fluids. Equilibrated Kt/V (eKt/V) is a metric used to account for the overestimation inherent to spKt/V and is derived by sampling postdialysis blood 30 minutes following dialysis as opposed to immediately at the end of treatment. However, there is no empiric evidence to suggest that outcomes are superior when eKt/V-as opposed to spKt/V-is used to gauge dialysis adequacy. Moreover, there are logistical barriers to sampling blood 30 minutes after dialysis, including considerations of shift turnover and patient travel. Perhaps for these reasons, eKt/V has not seen widespread clinical adoption in the United States. However, for adherents, it may be possible to convert spKt/V thresholds to eKt/V: eKt/V is typically between 0. Middle Molecule Clearance Up to this point, we have considered dialysis adequacy only in terms of lowmolecular-weight solute clearance, or more accurately, solutes whose kinetic behavior mimics that of urea. In contrast, "middle molecules" are a group of compounds that are biologically relevant but that are removed less efficiently by dialysis. The name middlemolecules harkens to the molecular weight of many such compounds that are middling in nature: falling between that of urea and other compounds readily cleared across dialytic membranes and that of proteins and glycoproteins that are typically too large to dialyze off. However, middle molecules also encompass lowmolecular-weight compounds that are inefficiently removed during dialysis either due to polyvalence (which limits dialytic membrane flux), protein binding, or intracellular sequestration. The effects of certain middle molecules such as phosphate and 2-microglobulin have been extensively studied. Emerging evidence suggests that metabolic byproducts such as p-cresol sulfate, indoxyl sulfate, methylamine, and dimethylamine may be relevant uremic solutes, but these have received comparatively less study. It is clear, however, that despite nearly four decades of research, there is no comprehensive litany of middle molecules. Nor is it certain-and, in reality, it is unlikely-that all middle molecules will behave similarly to one another with respect to dialytic removal. At present, there is no reliable means by which to consider middle molecules into the calculus of dialysis adequacy. Fluid Removal All too often, canonical dialysis "adequacy" (meaning low molecular weight clearance) and fluid removal are considered in parallel. Textbooks draw the distinction between solute clearance, which is predominantly diffusive in nature, and fluid removal which is convective. Trainees are typically taught that treatment time is determined by Kt/V considerations and fluid status by specification of target weight. TheDialysisPrescription 279 In a bygone era, this simplistic heuristic was seemingly reasonable. This is evidenced by the trend in mean dialysis treatment times in the United States, which fell from 6 hours or more in the early 1970s to 3 hours by the late 1980s. Greater dialyzer efficiency coupled with a urea-centric paradigm for determining treatment times implies the need for more rapid ultrafiltration during dialysis. Greater ultrafiltration rate portends both labile blood pressure during dialysis and frank intradialytic hypotension, which, in turn, are associated with transient interruptions in end organ perfusion. Until recently, it was believed that such phenomena were clinically relevant only inasmuch as they triggered overt clinical events or patient symptoms. However, converging lines of research indicate that the accumulation of subtle insults from subclinical events is of importance. Additional data demonstrate that transient interruptions in perfusion, often asymptomatic in nature, contribute substantively to transient myocardial stunning and white matter damage, which in turn are associated with cardiovascular events and neurocognitive deficits, respectively. Viewed in this light, it is not surprising that more rapid ultrafiltration is associated with a greater risk of mortality, particular cardiovascular mortality. In theory, such observations could be confounded because greater interdialytic weight gain both implies more rapid ultrafiltration and independently associates with poor prognosis. However, matched-pair analysis indicates that even if patients are exactly matched on interdialytic weight gain (and body weight), those with the higher ultrafiltration rate. Importantly, ultrafiltration rate is defined above in terms of volume removed per unit time per kilogram of body weight. Associations between absolute ultrafiltration rate, defined as volume removed per unit time-not indexed to body weight-is less clearly associated with clinical outcomes (unpublished observation). In essence then, the relevant parameter is related to how rapidly fluid is being removed relative to total body water (perhaps more accurately to extracellular volume although dedicated studies in this regard have not been conducted). This construct fits well into the framework of interruption of end-organ perfusion. As well, this may partially underlie the body weight paradox of dialysis whereby smaller patients consistently demonstrate poorer survival than larger patients. Differences in interdialytic weight between smaller and larger patients are comparatively less than differences in time needed to achieve spKt/V targets; thereby, smaller patients tend to have higher ultrafiltration rates on average than do larger patients. Best available evidence suggests that risk begins to inflect when the ultrafiltration rate crosses 10 mL/h/kg body weight and becomes statistically significantly elevated when in excess of 13 mL/h/kg body weight. At present, several 280 TheDialysisPrescription bodies are suggesting that guidelines for maximal Kt/V rate be incorporated into assessment of facility quality and remuneration. Of note, ultrafiltration rate has been studied as an average rate for dialysis sessions: net fluid removal divided by total treatment time indexed to body weight. There has been no directed study of whether techniques in which ultrafiltration rate is varied over the course of treatment, such as ultrafiltration profiling, sequential ultrafiltration-hemodialysis, or biofeedback technologies, modulate associations. The sobering reality is that patients do not want more dialysis whether in the form of longer or more frequent treatments. In a recent survey, fewer than onequarter of respondents indicated a willingness to extend treatment time by 30 minutes and fewer than one-eighth indicated that they would increase the frequency of dialysis. Clearly, additional patient education is needed to underscore the benefits of mitigating implied fluid removal rates. These include wearable ultrafiltration devices and drugs that block the uptake of sodium from the gut. Although such therapies are unlikely to fundamentally alter the association between ultrafiltration rate and outcome, they hold promise to reduce the net need for ultrafiltration during dialysis, which may enable reduction in treatment times in a safe and tolerable level. However, rigorous studies are needed to delineate the safety and efficacy of such treatments and to determine how they are incorporated into the fabric of clinical care. Conclusion In conclusion, urea kinetics-specifically the achievement of a spKt/V of 1. Emerging evidence indicates that the prescription should also imply a tolerable ultrafiltration rate-optimally less than 10 mL/h/kg but certainly no more than 13 mL/h/kg. Available data do not inform with respect to how best to incorporate middle-molecule clearance into the dialysis prescription, but the reader is advised to monitor the literature for advances in this regard. Finally, as in all of clinical medicine, care should be tailored to individual patients based on circumstances and preferences rather than in a cookie-cutter approach. Second generation logarithmic estimates of single-pool variable volume Kt/V: an analysis of error. The risks of high ultrafiltration rate in chronic hemodialysis: implications for patient care. Effect of the hemodialysis prescription of patient morbidity: report from the National Cooperative Dialysis Study. Initially envisioned to provide needed coverage for a few thousand patients through Medicare, it was anticipated that the program would not only provide life-sustaining dialysis therapy but would also result in patients returning to full, active, productive lives, including a return to employment. In 2012, there were more than 430,000 patients on various forms of dialysis, and although the growth rate of this population may be slowing, the complexity of the patients receiving this high-cost, technically complex treatment is increasing. Patients are receiving 8 to 10 different medications daily, and the current most common form of dialysis, thrice-weekly in-center hemodialysis, replaces the equivalent of 10% to 14% of small-solute removal compared with natural kidneys. The ability of conventional dialysis to remove the full range of toxins necessary to optimize health, including salt and water, is inadequate. Mortality remains greater than 18% annually overall and nearly 40% for patients new to dialysis, with an average of nearly two hospitalizations still occurring per patient per year. To date, quality improvement has been largely focused on biochemical or surrogate outcomes, as has been attempted with other disease states. Ironically, despite the clear value shown in the demonstration project for certain interventions such as oral nutritional supplements in selected patients, such supplements remain an uncovered benefit in the current reimbursement system and must be provided by dialysis facilities at their own expense. Recent publications show wide agreement within the nephrology community that care coordination incorporating nephrologist leadership is a promising approach to significantly improving outcomes. Care coordination as a delivery model is fundamental to improving outcomes by itself it will not ensure the goal-improving the lives of patients with kidney disease-without consensus on the key clinical targets and metrics to drive to this goal. Outcomes related to hospitalizations and mortality use standardized ratios, comparing actual with "expected" outcomes. The latter, however, are not based on transparent adjusters, and reliance on comorbidity data from the 2728 Medical Evidence forms adds to the inaccuracy. As Stephen Covey, the business leader and author pointed out: "Begin with the end in mind. Fundamental outcomes are necessary but not sufficient to climb the pyramid through complex programs to achieve lower mortality rates, fewer hospitalizations, and enhanced patient experience of care. Although some patients may state that they cherish length of life more than anything, the vast majority focus on the quality rather than the quantity of life as most important.

The level 3 technique is similar to the second anxiety facts buy cheap atarax 10mg on line, but fluid balance is tailored to achieve a targeted hemodynamic parameter every hour anxiety symptoms arm pain 10mg atarax otc. The choice of which modality to use is based largely on available resources and experience with a specific modality anxiety guru purchase atarax online. Newer anxiety symptoms 3 days buy atarax 10 mg on-line, high-flux membranes have the ability to remove inflammatory mediators anxiety attack symptoms yahoo buy atarax once a day, such as cytokines and chemokines anxiety job interview cheap 25mg atarax with amex, by convection. In 2012, Atan et al performed a systematic review of ex vivo studies on cytokine removal using extracorporeal circulation modalities. They found standard hemofiltration led to insignificant removal of most cytokines. High cutoff membranes, which have larger pore sizes, have better cytokine removal compared with standard high-flux membranes; this has been noted in ex vivo studies, animal experiments, and preliminary clinical studies. They also have favorable effects on immune cell function and increase survival in animal models of sepsis. More studies of the use of these membranes for septic shock patients are needed, however. To attenuate the problem of dialysis dysequilibrium, hypertonic saline infusions have been used. High-dialysate sodium concentrations or addition of sodium to replacement solutions is the key. It is recommended that a sodium concentration of at least 140 mEq/L be used during treatment, although a target of about 150 to 160 mEq/L is the usual. There is also a case report on the use of trisodium citrate to aid in sustaining hypernatremia and providing regional anticoagulation; changes in the composition of the replacement fluid can be made to compensate for alkalosis or hypocalcemia that may occur because of the trisodium citrate. Patients often develop hypotension and diuretic resistance, requiring higher doses of diuretics. Hypo- and Hypernatremia the above is especially true for sodium disturbances that are chronic. Sodium content in replacement fluid is 140 mEq/L, so to correct hyponatremia, 5% dextrose in water (D5W) can be infused separately to slowly increase sodium levels. As an example: Target sodium concentration = 123 mEq/L Replacement fluid sodium content = 140 mEq/L D5W sodium content, peripheral = 0 mEq/L Desired clearance = 2. As an example: Target sodium concentration = 150 mEq/L Replacement fluid sodium content = 140 mEq/L NaCl 3% sodium content, peripheral = 513 mEq/L Desired clearance = 2. This is performed by increasing the volume of replacement or dialysate solution and using solution with zero or low (2 mEq/L) potassium concentration. These fluids do not contain phosphate so calcium-based phosphate binder or other phosphate binders can be used if hyperphosphatemia occurs. It results from the inability to regenerate bicarbonate and excrete ammonium ions. Bicarbonate, lactate, citrate, and acetate are the four buffers in dialysis and replacement solutions used to treat acidosis. Acetate, however, is no longer used because it negatively affects hemodynamics and does not correct acidosis as well as the other buffers. Caveats to its use include liver failure, lactic acidosis, and shock because it can accumulate and not be converted to bicarbonate. Its use can lead to metabolic alkalosis, especially in higher doses because 1 mmol of citrate is converted to 3 mmol of bicarbonate. Again, caution should be used in patients with liver failure because its conversion to bicarbonate may be decreased. It should be managed by decreasing the bicarbonate concentration in solutions to the lowest concentration available. Chloride concentration in solutions should also be increased, and if sodium levels are high, sodium concentration should be decreased. These patients are often treated with permissive hypercapnia, which leads to respiratory acidosis. Respiratory alkalosis is treated like metabolic alkalosis, by decreasing the bicarbonate concentration in solutions to maintain normal pH. The mainstay of treatment is administration of normal saline to enhance elimination. They also noted that rebound did not occur and concluded that it could be used when chronic poisoning occurred. Treatment should be continued until there is clinical improvement or the concentration is less than 1 mEq/L. Toxicity can lead to multiorgan dysfunction, especially metabolic acidosis and neurotoxicity. Treatment cessation is indicated if there is clinical improvement, if concentration is less than 19 mg/dL, or if treatment has lasted at least 4 to 6 hours when salicylate levels are not available. Toxicity may present with ataxia, seizures, tremors, drowsiness, slurred speech, or oliguria. Treatment can be stopped after clinical improvement is noted or when the concentration is less than 10 mg/dL. These markers may be misleading because their levels can be influenced by patient factors such as nutritional status, fluid accumulation, and medication usage. Common complications after placement include hematoma, hemothorax, and pneumothorax, thrombus formation, pericardial tamponade, air embolism, and retroperitoneal hemorrhage. Catheter-line infections are also a concern and should be avoided by placement under sterile technique and appropriate dressing and catheter care. The use of topical antibiotics at the skin insertion site and use of antibiotic locks are not suggested because they may promote fungal infections and antimicrobial resistance. This occurs because replacement fluids and dialysate are not warmed, leading to cooling of core body temperature. Body temperature cooling can mask fevers, delaying infection recognition and treatment. In some instances, however, such as hyperthermia, after cardiac arrest, or with brain injury, this cooling effect may be advantageous. The extracorporeal circuit or filter membrane may activate inflammatory immune mediators, including various cytokines, which may increase protein breakdown and energy expenditure. As mentioned earlier, rarely, anaphylactoid reactions caused by bradykinin activation do occur. Complications of anticoagulation include the risk of bleeding, especially if systemic anticoagulation, such as with heparin, is used. Regional anticoagulation with citrate has less bleeding risk but has its own set of possible complications: hypocalcemia (citrate binds calcium), metabolic alkalosis (citrate is metabolized to bicarbonate), and hypernatremia (when sodium citrate is used). Citrate toxicity is noted by an increase in the total serum calcium, decrease in ionized calcium concentration, metabolic acidosis, and increased anion gap; if the ratio of total serum calcium to ionized calcium is greater than 2. To correct this, the citrate infusion should be decreased or stopped, the dialysate flow rate should be increased, and the calcium infusion should be increased. Careful monitoring should be carried out with the circuit-ionized calcium kept between 0. Monitoring of electrolytes, circuit- and patient-ionized calcium, and blood gases should occur at least every 6 hours, and total calcium levels should be measured at least once daily. Electrolyte complications result from their removal by dialysis or hemofiltration and insufficient replacement occurs, as well as from the use of citrate anticoagulation, as noted earlier. If severe derangements are present, laboratory measurements should be done frequently, about every 2 to 4 hours. Otherwise, electrolytes can be monitored at least every 6 hours, but this can be decreased to every 12 hours when they are stable. When managing fluid issues, the potential for volume depletion needs to be kept in mind. This can occur if there is inadequate monitoring or inaccurate calculations are performed. Vigilant monitoring is important because there is the potential to remove large volumes of fluid quickly. To prevent this, flow sheets for recording and monitoring fluid balance should be used. Also, a nurse-to-patient ratio of at least one to one is needed to ensure appropriate management. Severe protein-energy wasting ensues, leading to loss of lean body mass, Table 28. Continuous renal replacement therapy: cause and treatment of electrolyte complications. Dialysate and replacement solutions contribute up to 40 to 80 g/day, although they do not usually lead to hyperglycemia. If glucose-free solutions are used, there is a risk of hypoglycemia or inadequate nutrition. Their supplementation has not shown benefit on survival, but they are still replaced, especially because water-soluble vitamins and active vitamin D are easily depleted. Of note, vitamin A supplementation is not recommended because its accumulation can be toxic. In addition, vitamin C intake should not exceed the recommended daily dose because it can lead to oxalosis. Therefore, patients may be underdosed, especially with regard to antimicrobials, vasoactive medications, sedatives and paralytics, or antiseizure medications. Medications should be titrated based on effect, or when available, medication levels in the blood should be followed to adjust doses. While in the hospital, the mortality rate was about 61%; after discharge, about 28% of patients died. Other reviews and observational studies that have shown worse outcomes seem to be associated with greater burden of illness, multiple organ involvement, and hemodynamic instability. In addition, infant survival has been consistent between about 35% to 45%, and infants weighing less than 3 kg have worse survival, around 24% compared with infants over 3 kg (41%) as reported by Symons et al in 2003. Continuous renal replacement therapy outcomes in acute kidney injury and end-stage renal disease: a cohort study. Management of a severe carbamazepine overdose using albumin-enhanced continuous venovenous hemodialysis. Techniques of extracorporeal cytokine removal: a systematic review of the literature. Techniques of extracorporeal cytokine removal: a systematic review of the literature on animal experimental studies. Septic acute kidney injury in critically ill patients: clinical characteristics and outcomes. Variability in uremic control during continuous venovenous hemodiafiltration in trauma patients. Acute renal failure in intensive care units-causes, outcome, and prognostic factors of hospital mortality; a prospective, multicenter study. Shows that hospital mortality rate of patients with severe acute renal failure in patients requiring intensivecareremainshigh. High-volume hemofiltration for septic acute kidney injury: a systematic review and meta-analysis. This takes into account filter function, filter duration, and effective time of treatment. Continuous renal replacement therapies in patients with acute neurological injury. Economics of dialysis dependence following renal replacement therapy for critically ill acute kidney injury patients. Specific nutritional problems in acute kidney injury, treated with non-dialysis and dialytic modalities. Early initiation of continuous renal replacement therapy improves clinical outcomes in patients with acute respiratory distress syndrome. Fluid overload at initiation of renal replacement therapy is associated with lack of renal recovery in patients with acute kidney injury. Nutritional and metabolic alterations during continuous renal replacement therapy. A comparison of early versus late initiation of renal replacement therapy in critically ill patients with acute kidney injury: a systematic review and meta-analysis. Continuous renal replacement therapy does not have a clear role in the treatment of poisoning. Lithium poisoning treated by high-performance continuous arteriovenous and venovenous hemodiafiltration. Timing of initiation of dialysis in critically ill patients with acute kidney injury. Efficacy of continuous hemodiafiltration with a cytokine-adsorbing hemofilter in the treatment of acute respiratory distress syndrome. Evidence-based recommendations for macronutrient and micronutrient requirements are provided. Patient characteristics, dialysis status, and major outcomes were determined and stratified by clinical site. Found that in critically ill patients with acute renal failure, there are a large burden of comorbid disease, extensive extrarenal complications, and the need for dialysis in the majority of patients. A randomized trial of catheters of different lengths to achieve right atrium versus superior vena cava placement for continuous renal replacement therapy.