Joseph V. Bonventre, MD, PhD

• Renal Division, Department of Medicine, Brigham and
• Women's Hospital, Boston, MA
• Acute Kidney Injury: Biomarkers from Bench to Bedside

Portal osmopressor mechanism linked to transient receptor potential vanilloid 4 and blood pressure control pain treatment in osteoarthritis imdur 40mg on-line. In contrast pain treatment center albany ky generic imdur 40mg without a prescription, when NaCl is retained because the effective arterial blood volume is reduced knee pain treatment yoga buy imdur with amex, oedema results pain medication used for uti order 40 mg imdur amex. Regardless of its cause treatment of neuropathic pain guidelines generic imdur 40 mg without a prescription, symptomatic oedema often requires treatment with diuretics pain treatment with acupuncture discount imdur master card. Diuretics now comprise two classes, the natriuretics and the aquaretics, although diuretic treatment of oedema typically relies primarily on natriuretic diuretics. In addition to their use for oedema, diuretic drugs are indicated for a wide variety of non-oedematous disorders. Treatment of hypertension, nephrolithiasis (see Chapter 30), and hyponatraemia (see Chapter 28) are discussed elsewhere. This chapter will focus on renal mechanisms of diuretic action and diuretic therapy of oedema. The molecular targets of diuretic drugs are predominantly Na+ transport pathways at the apical (luminal) surface of kidney tubule cells. Mannitol is freely filtered at the glomerulus and its presence in tubule fluid minimizes passive water reabsorption. When an osmotic diuretic is administered, the osmotic force of the non-reabsorbable solute in the lumen opposes the osmotic force produced by sodium reabsorption, and sodium reabsorption eventually stops. Perhaps surprisingly, mannitol has a greater effect on inhibiting Na and water reabsorption in the loop of Henle than in the proximal tubule. Further downstream, in the collecting duct, mannitol also can reduce sodium and water reabsorption (Buerkert et al. During the administration of mannitol, its molecules diffuse from the blood stream into the interstitial space. Renal cortical and medullary blood flow rates increase following mannitol infusion (Buerkert et al. Experimental studies indicate that the osmotic effect of mannitol to increase water movement from intracellular to extracellular space leads to a decrease in haematocrit and in blood viscosity. Of the filtered load, < 10% is reabsorbed by the renal tubule, and a similar quantity is metabolized, probably in the liver. Osmotic diuretics Osmotic diuretics are substances that are freely filtered at the glomerulus, but are poorly reabsorbed. Inhibition of NaCl reabsorption by these drugs depends on the osmotic pressure exerted by the drug molecules in solution, not on interaction with specific transport proteins. Because the relationship between the magnitude of diuretic effect and concentration of osmotic diuretic in solution is linear, all osmotic diuretics are small molecules. Although osmotic agents do not act directly on transport pathways, ion transport is affected. Following mannitol infusion, sodium, potassium, calcium, magnesium, bicarbonate and chloride excretion rates increase (Table 33. Sodium and water reabsorption rates are reduced by 27% and 12%, respectively (Seely and Dirks, 1969). Magnesium and calcium reabsorption is also reduced along the proximal tubule and loop of Henle. Carbonic anhydrase inhibitors also increase potassium excretion, likely indirectly. The effect of carbonic anhydrase inhibitors on the proximal tubule ion transport facilitates an increase in tubular fluid flow rate and sodium and bicarbonate delivery to the distal nephron, where the lumen negative voltage (Malnic et al. The biochemical, morphological, and functional properties of carbonic anhydrase have been reviewed (Pastorekova et al. Normally the proximal tubule reabsorbs 80% of the filtered load of bicarbonate and 60% of the filtered load of sodium chloride via cellular mechanisms depicted in. Carbonic anhydrase inhibitors act primarily in this segment, yet their natriuretic potency is relatively weak. First, proximal sodium reabsorption is mediated by carbonic anhydrase-independent as well as carbonic anhydrase-dependent pathways. Second, the increased sodium delivered to distal nephron segments is largely reabsorbed. Third, carbonic anhydrase inhibitors generate a hyperchloraemic metabolic acidosis, further reducing the effects of subsequent doses of carbonic anhydrase inhibitor. Finally, metabolic acidosis increases the Ki for bicarbonate absorption by membrane impermeant carbonic anhydrase inhibitors by a factor of 100 to 500, suggesting that metabolic acidosis is associated with changes in the physical properties of the carbonic anhydrase protein (Shuichi and Schwartz. For these reasons, carbonic anhydrase inhibitors alone are rarely used as diuretic agents chronically; they do, however, play an important role in short-term treatment of diuretic resistance. The highest concentrations are found in tissues that contain large amounts of carbonic anhydrase. Renal effects are noticeable within 30 minutes and are usually maximal at 2 hours. Acetazolamide is not metabolized, but is excreted rapidly by glomerular filtration and proximal tubular secretion. The half-life is approximately 5 hours and renal excretion is essentially complete in 24 hours (Weiner, 1990). Generally, carbonic anhydrase inhibitors are well tolerated with infrequent serious adverse effects. Side effects of carbonic anhydrase inhibitors may arise from the continued excretion of electrolytes. Even though carbonic anhydrase inhibitors do not increase urinary calcium excretion, they do increase the risk for nephrocalcinosis and nephrolithiasis, owing to their effects on urine pH and citrate excretion. Premature infants treated with furosemide and acetazolamide are particularly susceptible to nephrocalcinosis, presumably due to the combined effect of an alkaline urine and hypercalciuria (Stafstrom et al. Loop diuretics the loop diuretics inhibit sodium and chloride transport along the loop of Henle and macula densa. Although these drugs also impair ion transport by proximal and distal tubules under some conditions, these effects probably contribute little to their action clinically. The loop diuretics available include furosemide, bumetanide, torsemide, and ethacrynic acid. Loop diuretics increase water, Na+, K+, Cl-, phosphate, magnesium, and calcium excretion rates (Table 33. During maximal loop diuretic action, the urinary + concentration is usually between 75 and 100 mmol/L (Puschett Na and Goldberg, 1968). This effect of loop diuretics has been exploited to treat hyponatraemia, when combined with normal or hypertonic saline (Hantman et al. This transporter is a member of the cation chloride cotransporter family (Hebert et al. This protein uses the electrochemical gradient favouring Na+ entry across the apical membrane to move Cl- into the cell along with K+, while K+ diffuses back into the luminal fluid via a K+ channel; thus, net reabsorption across this segment is primarily NaCl. The combination of K+ movement across the apical membrane and Cl- movement across the basolateral cell membrane generates a transepithelial voltage oriented in the lumen-positive direction (Greger and Schlatter, 1983), which drives absorption of Na+, Ca2+ and Mg2+ via the paracellular pathway. It should be noted, however, that both the transcellular and the paracellular components of Na+ transport are inhibited by loop diuretics, the former directly and the latter indirectly. The combination of solute absorption and water impermeability determines the role of the thick ascending limb as the primary diluting segment of the kidney. Thick ascending limb cells have been shown to produce prostaglandin E2 following stimulation with furosemide (Miyanoshita et al. Blockade of cyclooxygenase reduces the effects of furosemide to inhibit loop segment chloride transport in rats (Kirchner, 1985; Kirchner et al. When given intravenously, peak diuretic concentrations are reached rapidly, but levels may decline more rapidly than during oral administration. As natriuresis depends on the time above the natriuretic threshold, and as the threshold is impacted by disease (A), the relationship between oral and intravenous efficacy is complex. Increases in renal prostaglandins may also contribute to the haemodynamic effects of loop diuretics described below. Ca2+ and Mg2+ transport Loop diuretics increase the excretion of the divalent cations, calcium and magnesium, owing to their effects to reduce the transepithelial voltage. When loop diuretics are present, the cells cannot sense luminal NaCl and renin secretion cannot be suppressed. Acute intravenous administration of loop diuretics increases venous capacitance (Dikshit et al. Although venodilation and improvements in cardiac haemodynamics frequently result from intravenous therapy with loop diuretics, the haemodynamic response to intravenous loop diuretics may be more complex (Ellison, 1997b). The effects of renal denervation on sympathetic responses to furosemide were studied. The three loop diuretics that are used most commonly, furosemide, bumetanide, and torsemide, are absorbed quickly after oral administration, reaching peak concentrations within 0. Furosemide absorption is slower than its elimination in normal subjects; thus the time to reach peak serum level is slower for furosemide than for bumetanide and torsemide. Loop diuretics are organic anions that circulate tightly bound to albumin (> 95%), thus their volume of distribution is small except during extreme hypoalbuminaemia (Inoue et al. Approximately 50% of an administered dose of furosemide is excreted unchanged into the urine. The remainder appears to be eliminated by glucuronidation, probably by the kidney. Torsemide and bumetanide are eliminated both by hepatic processes and through renal excretion. The differences in metabolic fate mean that the half-life of furosemide is altered by kidney failure more than the half-lives of torsemide and bumetanide. Loop diuretics gain access to the tubular fluid almost exclusively by proximal secretion. First, they increase the excretion of urine that is bicarbonate free but contains Na+ and Cl-. Second, loop diuretics directly inhibit transport of Na+ and Cl- into thick ascending limb cells, which may stimulate H+ secretion via Na+/H+ exchange (Good et al. Hypokalaemia itself also contributes to metabolic alkalosis by increasing ammonium production (Tannen, 1970), stimulating bicarbonate reabsorption by proximal tubules (Soleimani et al. Some of these effects may be offset because loop diuretics also strongly increase the expression and activity of pendrin, a chloride/bicarbonate exchanger expressed by type B intercalated cells (Quentin et al. Ototoxicity with deafness is the most common toxic effect of loop diuretics unrelated to their effects on the kidney. It appears likely that all loop diuretics cause ototoxicity, because ototoxicity can occur during use of chemically dissimilar drugs such as furosemide and ethacrynic acid (Maher and Schreiner, 1965; Nochy et al. The stria vascularis, which is responsible for maintaining endolymphatic potential and ion balance, appears to be a primary target for toxicity (Ikeda et al. A characteristic finding in loop diuretic ototoxicity is strial oedema, because an isoform of the Na-K-2Cl cotransporter in expressed there (Mizuta et al. Loop diuretics cause loss of outer hair cells in the basal turn of the cochlea, rupture of endothelial layers, cystic formation in the stria vascularis, and marginal cell oedema in the stria vascularis (Ryback, 1993). Ototoxicity appears to be related to the peak serum concentration of loop diuretic and therefore tends to occur during rapid drug infusion of high doses. For this reason, this complication is most common in patients with uraemia (Star, 1997). It has been recommended that furosemide infusion be no more rapid than 4 mg/ minute (Wigand and Heidland, 1971). In addition to those with renal failure, infants, patients with cirrhosis, and patients receiving aminoglycosides or cis-platinum may be at increased risk for ototoxicity (Star, 1997). The most common adverse effects of loop diuretics result from their primary actions. Overzealous diuretic usage or intercurrent complicating illnesses can lead to excessive contraction of the intravascular volume with orthostatic hypotension, renal dysfunction, and sympathetic overactivity. Disorders of Na+ and K+ concentration are among the most frequent adverse effects of loop diuretics. Hyponatraemia is less common with loop diuretics than with distal convoluted tubule diuretics (see later), but can occur. Additional factors that may contribute include the non-osmotic release of arginine vasopressin (Bichet et al. Hypokalaemia occurs commonly during therapy with loop diuretics, although the magnitude is smaller than that induced by distal convoluted tubule diuretic (loop diuretics, 0. Loop diuretics increase the delivery of potassium to the distal tubule, because they block potassium reabsorption via the Na-K2Cl cotransporter. Although this effect occurs during acute treatment (as during intravenous chlorothiazide administration), it probably contributes relatively little to overall natriuresis during chronic use (Kunau et al. There is some evidence that thiazides inhibit solute transport in medullary collecting tubules of rats (Wilson et al. Stimulation of distal calcium reabsorption is accompanied by an increase in intracellular calcium activity, suggesting that a primary effect is to increase apical calcium entry (Gesek and Friedman, 1992). The Na/Ca exchanger is electrogenic, and when the intracellular Na+ concentration declines, the electrochemical driving force favouring calcium movement from cell to interstitium increases.

Cremation Cremation Regulations (2008) require two doctors to complete a certificate to establish identity and that the cause of death is not suspicious before a person can be cremated chronic pain treatment center venice fl order 40mg imdur with mastercard. Notification of death to the coroner the coroner can be contacted via the local police nerve pain treatment back purchase imdur uk. People live with chronic disease for decades and ageing with chronic disease has become the norm southern california pain treatment center pasadena buy imdur 20 mg on line. There is support for moving towards a dynamic concept of health based on restoring integrity back pain treatment videos generic imdur 40 mg amex, equilibrium allied pain treatment center pittsburgh buy imdur 40mg cheap, & well-being through self-management-the ability to `adapt and to self-manage cape fear pain treatment center lumberton nc generic 20mg imdur fast delivery. With wealth comes more stable political systems, and these are what are necessary for literacy and education to flourish, which in turn lead to easy access to clean water (the key issue, as more than 1 billion people have no such access) and the possibility of developing equitable health delivery systems. So, resources should preferably be distributed in relation to need, within a society that has equal access. Similarly in the army, there is a 5-fold difference in mortality from heart disease between highest and lowest ranks. Illness makes us descend the social scale, but this effect is probably not big enough to account for the observed differences between classes. However, it is more likely that differences are due to smoking, education, diet, poverty, stress, and overcrowding. Health is not purely a biological process but a combination of biological, psychological, and social factors. The traditional biomedical model assumes that all illness can be traced back to a single disorder of a part of the body and that all symptoms are due to disease within the body. Does illness arise from a disease which affects only a part of the whole body, or from a problem at the level of the whole person within their situation In relation to illness, the reductionist biomedical model assumes there must always be a disorder of a part of the whole, and does not consider that the whole person may be ill without any specific part of the person being abnormal. A holistic approach to illness acknowledges objective scientific explanations of physiology, but also admits that people have inner experiences that are subjective, mystical (and, for some, religious), which may affect their health and health beliefs. It means helping patients make choices concerning their own care, and co-ordinating this across an increasingly complicated health and social care system. How to do it: Supporting individuals to change behaviour, eg through brief advice during a consultation (Have you ever thought about giving up smoking Secondary prevention Secondary prevention is systematically detecting the early stages of disease and intervening before symptoms develop-eg treating hypertension and prescribing statins to reduce cardiovascular disease. Successful secondary prevention improves life expectancy and reduces complications of disease. Try to engage with and provide services to patients who are not reached by mainstream services. Tertiary prevention aims to reduce the impact of the disease by preventing disease-related complications eg retinal photography in diabetes. It provides an alluring means of escape without entailing too headlong a rush into the seductive arms of death. The price of this is that patient-centred activities are crowded out, and that, with many preventive activities offered, no guidance on prioritizing individual intervention is forthcoming. Another example of logistical barriers is providing a sequence of working fridges in the distribution of vaccines to rural tropical areas. Political barriers It is not unknown for governments to back out of preventive obligations as if influenced by groups who would lose if prevention were successful. Motivation barriers Changing from a crisis-led work pattern to strategic prevention is one way that practice nurses can lead the way. We are all guilty of exaggerating benefits and avoiding discussion of controversial areas with patients. If screening is to be done at all, it makes economic sense to do it in primary care. Health education presumes that people are rational and want to promote their own survival. A gruesome film about the worst effects of dental caries produces petrified immobility, not self-help or trips to dentists. Compared with parents, teacher-based oral health education has a better effect on oral health (at least in middle-school Chinese students). As Chinese thought reformers knew so well, attitude changes depend on a high level of emotional involvement. Objective feedback Giving standard written advice about physical activity helps promote exercise. So peereducation has been developed as a tool to reach certain groups, and evidence suggests that this is promising. Use of inhalants fell by more than 32% in elementary schools and by ~20% in high schools. Lifestyle advice: Stop smoking; weight loss if overweight; eat a healthy diet; keep alcohol within recommended limits; encourage physical activity. The smoking in public places ban in England in 2007 is estimated to have helped 400,000 people quit. Varenicline (eg Champix) Smokers (>18yrs) start taking the tablets 1wk before the intended quit day (0. If the patient has stopped smoking after 12wks consider a further 12wk course to risk of relapse. Contraindications: Epilepsy, or risk of seizures, eating disorders, bipolar disorder. Only offer a further prescription if the patient demonstrates a continuing commitment to stop smoking. Helping people to cut down For specific treatment see p376 Time interventions for when motivation is maximal, eg as (or before) pregnancy starts. Management of drug misuse Aims to reduce drug-related morbidity and mortality; decrease risk of infectious diseases, and decrease criminal activity used to finance drug habits. Group and behavioural therapy: Group activities (eg Weight Watchers) have a higher success rate in producing and maintaining weight loss. Primary care Managing sleep problems Insomnia describes a perception of disturbed or inadequate sleep. It can adversely affect quality of life, concentration and memory, performance of daytime tasks and cause relationship problems. Many do not have a sleep problem themselves, but a relative feels there is a problem (eg the retired milkman who continues to wake at 4am). Up to 40% of people with insomnia are thought to selfmedicate with over-the-counter hypnotics that are available without prescription (eg sedative antihistamines). In the elderly: Exercise maintains functional capacity; levels of disability and risk of falls/hip fracture; and improves quality of sleep. This entails systems of interacting methods to restore and optimize health that have an ecological foundation, that are environmentally, economically and socially viable indefinitely, and that function harmoniously both with the human body and our wider environment, and that do not result in unfair or disproportionate impact on any ecosystem. But in many places the law is that, however unorthodox a practitioner may be, he or she cannot be convicted of unethical practice in the absence of clear harm. Some will feel unable to tell their doctor about trips to alternative therapists, unless asked. Modern medicine is criticized for sacrificing humanity to technology, and with little benefit for many people. In some circumstances a combination of the 2 mechanisms are likely to make it effective (eg back pain). Coercive behaviour: Act/pattern of acts of assault, threats, humiliation, and intimidation or other abuse used to harm, punish, or frighten victims. Prevalence Although men may be the victims of domestic violence, ~80% of reported domestic violence is against women by male partners. Domestic violence affects 1 in 4 women and is the most common form of inter-personal crime: 60%-current partner; 21%-former partner; half suffer >1 attack; 1 in 3 have been attacked repeatedly. Presentation General practice is often the first place in which victims seek formal help, but only 1 in 4 actually reveals the true nature of the problem. In time this might give them the confidence and back-up needed to break out of the situation. Management Talk through the situation with the patient, carer, and other services involved in care. There are 5 managerial functions: 1 Planning: Involves selecting missions and objectives, and the actions to achieve them-this requires decision-making 2 Organizing: Defining roles-ensuring all tasks necessary to accomplish goals are assigned to those people who can do them best 3 Staffing: Ensuring all positions in the organizational structure are filled with people able to fulfil those roles 4 Leading: Influencing people so that they will contribute to organization and group goals 5 Controlling: Measuring and correcting individual and organizational performance to ensure events conform to plans. As a result, consultations were written up in the wrong record, referrals made for the wrong patient, and prescriptions issued to the wrong person. We then introduced a pop-up alert which appears for any patient who has the same name as someone else in the practice to highlight that extra care is required in checking and selecting the correct record. Market-led models Well-capitalized companies take over running general practices, after winning provider contracts from Clinical Commissioning Groups. However, there are clear problems with corporate health care: the United States differs from other industrialized countries with its absence of universal health insurance coverage. It is the most expensive health care system in the world yet it consistently underperforms relative to other countries (eg on access, efficiency and equity), and fails to achieve better health outcomes. This is the model favoured by the Royal College of General Practitioners-as providing the most flexible model which can rapidly adapt to local priorities, 49 cause the least disruption to existing services-and maintain continuity of care. Protocols, targets, and guidelines There is nothing better (for the doctor and the patient) than doing a job for the love of it-and not many people love targets set by other people-so the target has to entail great benefits to outweigh its unintended consequences. Protocols, particularly if they have been handed down from some supposedly higher authority, have a reputation for being strict, sinister, and stultifying instruments for thought control. It is known that doctors working in highly regulated environments with strict protocols perform suboptimally. But when this has been evaluated in randomized trials, no impact could be detected. Be prepared to defend your deviation from a guideline should it ever be questioned. Within practices, individual doctors must consider their own professional development and educational needs. Resources should be provided to help develop clinical governance (eg protected time for audit, funding for courses and educational activities).

Many cases are apparent from the history and the clinical setting pain and treatment center greensburg pa discount 20 mg imdur with mastercard, but less obvious causes include surreptitious vomiting and laxative abuse pain treatment pregnancy order 40 mg imdur otc, which are frequently diagnostic challenges neck pain treatment physiotherapy purchase imdur 20 mg on-line. Erosion of the dental enamel pain solutions treatment center reviews 20 mg imdur with visa, metabolic alkalosis pain treatment center albany ky cheap imdur 40mg with amex, and low urinary chloride content are all features of chronic vomiting and clues to its diagnosis hip pain treatment exercises purchase 40mg imdur amex. In patients with self-induced diarrhoea from catharctics, the history of laxative use may be difficult to obtain. Habitual use of anthracene laxatives, such as senna, cascara, and aloe, leads to melanosis coli (Wittoesch et al. Phenolphthalein is a cathartic and has been previously used in laxatives that turns pink or purple in the presence of a strong alkali. Excessive potassium loss from the skin can result from prolonged exposure in hot environments where sweat loss is high, and this diagnosis should be apparent from the history. Bartter and Gitelman syndromes are rare genetic disorders that exhibit hypokalaemia and usually exhibit metabolic alkalosis with a normal or low blood pressure. However, a much more frequent cause for this constellation of findings is surreptitious diuretic abuse. A urine screen for diuretics is an important component of the evaluation of the patient with possible Bartter or Gitelman syndrome in order to exclude surreptitious diuretic use. Bartter and Gitelman syndrome can be differentiated from each other by assessment of urinary calcium excretion, which is high with Bartter syndrome and suppressed in Gitelman syndrome. Renal transport defects Genetic diseases of hypokalaemia are rare, but have advanced our understanding of renal physiology. In 1962, Bartter described the association of hypokalaemia, hypomagnesaemia, hyper-reninaemia, and metabolic alkalosis (Bartter et al. Further phenotypic refinement led to the recognition of two syndromes: Bartter syndrome and Gitelman syndrome (Gitelman et al. These three proteins are necessary for sodium reabsorption in the thick ascending limb of the loop of Henle (Simon et al. Gitelman syndrome features hypocalciuria, hypomagnesaemia, milder clinical manifestations, and it generally presents at a later age. This syndrome most commonly is due to mutations affecting the thiazide-sensitive NaCl cotransporter (Simon et al. Hypotension and intravascular volume depletion due to renal sodium-wasting are common features in both. Concomitant intravascular volume depletion and secondary hyperaldosteronism further exacerbates the hypokalaemia. Treatment of the hypokalaemia frequently involves oral administration of large amounts of potassium chloride, but some degree of hypokalaemia frequently persists. Liddle syndrome is associated with hypertension, hypokalaemia, metabolic alkalosis, and suppressed renin and aldosterone levels (Liddle et al. The absolute plasma aldosterone concentration in combination with the plasma aldosterone to plasma renin activity ratio has been used to differentiate these possibilities. If diuretic therapy is required, for example, in the treatment of hypertension or heart failure, concomitant use of a potassium-sparing diuretic, such as amiloride or triamterene, should be considered and the dietary sodium and potassium content reassessed. Hypomagnesaemia can lead to renal potassium wasting, and refractoriness to potassium replacement (Kamel et al. Correction of the hypokalaemia may not occur until the hypomagnesaemia is corrected (Shils, 1969). Patients with diuretic-induced hypokalaemia who are refractory to oral potassium chloride administration should be tested for hypomagnesaemia, and magnesium replacement therapy begun if indicated. The coexistence of other electrolyte abnormalities, particularly hypophosphataemia, should be also sought. For complete details of the evaluation and treatment of primary hyperaldosteronism refer to textbook chapters that deal with the diagnosis of hyperaldosteronism (Weiner and Wingo, 2010). Treatment of hypokalaemia the primary short-term risks of hypokalaemia is cardiovascular, and the most important effect in the short term is to predispose to cardiac arrhythmias. However, the primary risk of too rapid potassium replacement is the development of hyperkalaemia, with resultant ventricular fibrillation. Thus, the risks associated with hypokalaemia must be balanced against the risks of therapy when determining the appropriate approach to the patient. Whenever possible, replacement therapy should be administered orally, which allows endogenous gastrointestinal potassium sensors to monitor potassium repletion therapy (Morita et al. Situations that require emergent therapy are rare but may include the patient with severe hypokalaemia that requires emergent surgery, and the concern is heightened if the patient has known coronary artery disease or is receiving digitalis. Some retrospective studies have suggested that the incidence of intraoperative complications attributable to hypokalaemia is low (Hirsch et al. A second generally accepted indication for emergent therapy is patient with an acute myocardial infarction and significant ventricular ectopy. Finally, hypokalaemia is frequently associated with some degree of skeletal muscle weakness and with severe hypokalaemia frank paralysis can ensue with respiratory compromise which requires urgent treatment. The choice of parenteral versus oral therapy usually depends on the ability of the patient to take oral medicine and a normally functioning gastrointestinal tract (Weiner and Wingo, 1997). However, such rates are rarely needed and oral replacement therapy is safer and is the preferred route of administration. The choice of parenteral fluids used for potassium administration can affect the response. Intravenous D-glucose administration increases serum insulin levels, which can stimulate cellular Hyperkalaemia Hyperkalaemia, when severe, has predictable effects on cardiac electrical conduction which make this condition a potentially lethal disorder; however, from a clinical perspective many cases of hyperkalaemia are asymptomatic. The assessment of hyperkalaemia includes exclusion of laboratory error and pseudohyperkalaemia, determination of the urgency for treatment, and institution of appropriate therapy. Long-term treatment requires identification of the aetiology and prevention of recurrence. Classification of hyperkalaemia Hyperkalaemia reflects impaired potassium clearance relative to potassium intake or an altered distribution between intra- and extracellular potassium, but chronic stable hyperkalaemia without a change in potassium intake indicates renal adaptation albeit at an abnormal plasma potassium concentration. To evaluate a patient with hyperkalaemia, one should consider four broad groups of aetiologies: pseudohyperkalaemia and laboratory artefacts, excessive intake, redistribution, and impaired renal potassium clearance. A careful history and physical examination in combination with selected laboratory tests is sufficient to differentiate most cases. Frequently, potassium concentration is measured in blood that has been allowed to clot and centrifuged to obtain the serum. Centrifuging the specimen before the clot has formed completely can increase the susceptibility of red blood cells to membrane damage during centrifugation. This can lead to leakage of potassium from erythrocytes and to development of pseudohyperkalaemia. Release of potassium from leucocytes and platelets can also cause pseudohyperkalaemia. With platelet counts between 500,000/cm3 and 1,000,000/cm3, 34% of patients exhibit pseudohyperkalaemia (Graber et al. Pseudohyperkalaemia should also be suspected if there is a family history of hyperkalaemia, or if conditions associated with significant leucocytosis or thrombocytosis are present. Rarely, pseudohyperkalaemia has been reported in association with rheumatoid arthritis (Ralston et al. Occasional families have abnormal red blood cell membrane potassium permeability, which leads to excessive potassium leakage rates and pseudohyperkalaemia (Stewart et al. Recognizing pseudo-hyperkalaemia is important, because it is purely a laboratory artefact and does not require specific therapy. Inappropriate treatment of pseudohyperkalaemia can result in serious hypokalaemia and increase the risk of hypokalaemia-related complications. Potassium intake Although abnormal renal potassium clearance is generally necessary for the development of persistent hyperkalaemia, excessive potassium intake is often an aggravating factor. Essentially all foods contain potassium, although the relative amounts of potassium differ greatly (Table 34. For example, as many as 4% of patients receiving potassium chloride supplements develop hyperkalaemia (Lawson, 1974). Thus, excessive potassium ingestion is an infrequent cause of hyperkalaemia in the absence of other contributing factors. However, if renal potassium excretion is impaired, whether through drugs, renal insufficiency, or other causes, then excess potassium intake can produce hyperkalaemia. It is important to recognize that the renal mechanisms which enable excretion of large amounts of potassium are much more sensitive to oral potassium intake than to intravenous potassium administration possibly due to gastrointestinal potassium sensors. Thus, the risk of acute hyperkalaemia with potassium supplementation is much greater with intravenous compared to oral potassium administration. Some studies estimate that 50% of all cases of hyperkalaemia are related to potassium supplements (Shapiro et al. Patients with renal failure who are receiving complete nutritional support through enteral nutritional supplements frequently develop hyperkalaemia. For intravenous hyperalimentation fluids, the potassium content recommended in normal individuals usually should be reduced when administered to patients with renal insufficiency, and frequent monitoring of the serum/plasma potassium concentration is recommended. Potassium supplements may provoke hyperkalaemia, especially if administered intravenously. They are ordered frequently for patients receiving diuretics who may also be receiving other drugs that predispose to hyperkalaemia. Potassium supplements may be prescribed with increasing frequency for conditions other than hypokalaemia, due to the recognition that potassium supplementation decreases blood pressure (Smith et al. Citrate can be supplied either as a sodium salt, potassium salt, or as a sodium-potassium salt (Table 34. Of note, potassium deficiency can cause or predispose to rhabdomyolysis, resulting in potassium liberation into the extracellular fluid compartment, which results in either normokalaemia or hyperkalaemia, despite total body potassium deficiency. Rhabdomyolysis is a cause of acute kidney injury that impairs renal potassium excretion potentially lead to lethal hyperkalaemia. Large amounts of potassium and nucleic acids are liberated in the treatment of rapidly proliferating lymphomas. Without prior hydration and volume expansion to preserve urine output, hyperkalaemia and uric acid acute kidney injury may ensue (Arrambide and Toto, 1993). Redistribution Several common clinical conditions are known to cause redistribution. In addition, less common causes of hyperkalaemia include drugs and conditions that affect membrane voltage. In diabetic ketoacidosis, hyperkalaemia is generally due to the lack of insulin-stimulated cellular potassium uptake and to the presence of glucose as an ineffective extracellular osmole (discussed in more detail below) and not the concomitant metabolic acidosis. Tissue necrosis Tissue necrosis can lead to hyperkalaemia, depending on the mass and the rapidity of the cell lysis. Common examples include rhabdomyolysis, ischaemic extremities or bowel and haemorrhage, particularly retroperitoneal haemorrhage. Rhabdomyolysis can result from crush injury, seizures, electrical shock, cocaine ingestion, sepsis, Table 34. Hyperglycaemia, if occurring in the absence of either sufficient insulin or tissue responsiveness to insulin, and mannitol, often used in neurosurgical patients, are common causes of hyperosmolality. Hypertonicity causes cell shrinkage, leading to stimulation of net cellular potassium efflux. Hyperosmolality from solutes that rapidly cross plasma membranes, such as urea, does not alter cellular volume and does not cause hyperkalaemia. In diabetic ketoacidosis the hyperglycaemia and attendant hyperosmolality may also contribute to the hyperkalaemia in addition to the insulinopenic state. Typically, they do so through predictable effects on hormone systems that regulate potassium homeostasis and renal transport mechanisms know to be involved in renal potassium excretion. Aldosterone, insulin, and -adrenergic agonists are known to affect the transcellular potassium distribution. The normal response to increased potassium intake is increased aldosterone synthesis, and aldosterone stimulates cellular potassium uptake. It can cause hyperkalaemia in a small percentage (~ 7%) of patients, particularly when given intravenously at high doses (Oster et al. Low-molecular-weight heparin has less effect on aldosterone synthesis and is less likely to cause hyperkalaemia. Spironolactone and eplerenone, clinically important mineralocorticoid receptor antagonists, inhibit aldosterone action at the cellular level. Increased use of spironolactone and eplerenone, in response to evidence that they decrease mortality in many patients with congestive heart failure, has resulted in a substantial increase in the number of patients being admitted with hyperkalaemia. Additionally, the progesterone agonist drospirenone used in some birth control pills can cause hyperkalaemia (Cremer et al. Cationic amino acids, such as arginine and lysine, can cause hyperkalaemia, probably by exchanging with cellular potassium. Fluoride intoxication can rarely cause of death due to hyperkalaemia (Baltazar et al. Persistent hyperkalaemia which is not due to laboratory artefact or redistribution thus almost always involves alteration in renal potassium clearance. Essentially all regulation of renal potassium excretion occurs in the renal collecting duct, and it proximal extension the initial collecting tubule. This is the site of action of many medicines which affect collecting duct potassium secretion (Table 34. Many drugs affect potassium clearance by chronically inhibiting potassium secretion, by either inhibiting aldosterone synthesis production or action, or by inhibiting the cellular processes necessary for collecting duct potassium secretion (see below). Mineralocorticoids play an important role regulating extracellular potassium concentration through both effects on cellular potassium redistribution and by enhancing the maximum capacity for potassium secretion by the aldosterone-sensitive distal nephron. The most common example is the skeletal muscle relaxant succinylcholine (Sterns et al. Hyperkalaemic periodic paralysis represents a rare form of period paralysis associated with weakness frequently provoked by exercise.

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