Anaphylaxis and Anaphylactoid Reactions

Anaphylaxis is a life-threatening allergic reaction that is rapid in onset and typified by symptoms such as hives, pruritus, angioedema, shortness of breath, wheezing, stridor, hypotension, shock, and cardiovascular collapse. Typically, the reaction is due to the release of inflammatory mediators and cytokines from mast cells and basophils that are usually triggered by immunoglobulin E (IgE) binding to an antigen in a sensitized host. Occasionally, nonimmunological mechanisms that lead to direct degranulation of mast cells and basophils (such as that seen with exposure to contrast media) can be operative, and these are termed anaphylactoid or nonimmune anaphylaxis . The World Health Organization defines anaphylaxis as when any one of the following three events occurs within minutes or, rarely, hours after exposure to a potential antigen: (1) involvement of the skin or mucosal tissue plus either respiratory difficulty or a low blood pressure causing symptoms; (2) two or more of the following symptoms after likely contact with an allergen: (a) involvement of the skin or mucosa, (b) respiratory difficulties, (c) low blood pressure, or (d) gastrointestinal (GI) symptoms; or (3) low blood pressure after exposure to a known antigen.

Dialysis patients are exposed to numerous antigens that could trigger a reaction, and symptoms may develop at any time during the treatment, although characteristic patterns may give clues as to the inciting agent. For example, symptoms that occur within the first 5 minutes after starting treatment point toward issues with the dialyzer, tubing, or dialysate. Symptoms may also be somewhat atypical in ESRD patients, and they include burning or heat sensation throughout the body or at the access site; dyspnea; chest pressure or tightness; angioedema/laryngeal edema; acral or oral paresthesia; rhinorrhea; lacrimation; sneezing or coughing; flushing; pruritus; and nausea/vomiting, abdominal cramps, and diarrhea. Any of these symptoms should prompt consideration that the patient may be having a reaction that requires prompt attention.

Reactions Associated With the Dialysis Circuit

Although reactions to the components of the dialysis circuit are uncommon, it is important to understand the risks associated with exposure of the patient’s blood to these components (including the blood tubing, dialysis membranes, sterilizing reagents, and dialysate solutions). In the recent past, acute reactions in patients undergoing HD were more common and were related to the use of bioincompatible, complement-activating dialysis membranes and acetate-containing dialysate solutions; exposure to polyacrylonitrile (PAN) dialysis membranes that stimulated the production of bradykinin; and ethylene oxide sterilization of dialyzers. Studies in the 1980s reported a frequency of approximately 1 reaction in every 12,000 HD episodes; more contemporary data are not available, but reactions are thought to be less frequent.

Allergic reactions occurring during dialysis can be classified by timing and severity: Type A reactions occur within the first 5 to 20 minutes of the HD session and patients develop typical anaphylaxis-type symptoms, whereas type B reactions occur later in the session and symptoms are milder. It has been thought that type A reactions are IgE mediated, whereas type B reactions are anaphylactoid and may be more related to activation of the complement cascade. Given that patients undergoing dialysis are exposed to numerous stimuli (dialysis membrane, dialysate, blood tubing lines, and medications), a careful and thorough assessment of these exposures must be undertaken in any patients who suffer a reaction.

Previously, ethylene oxide was routinely used as a gas sterilizer for dialysis membranes and could lead to IgE-mediated type A reactions. However, the use of ethylene oxide has dramatically decreased and most dialyzers are now sterilized with steam, electron beam, or γ radiation. Likewise, reactions to dialysis membranes were common when cellulose components were used. The cellulose fiber could activate the complement cascade, leading to type B reactions. However, most United States dialysis centers now use synthetic membranes (composed of polymethylmethacrylate, polyether sulfone, polysulfone, or PAN), which are biocompatible and have a much lower risk of reactions. Another source of reactions was seen when dialysis membranes underwent processing for reuse, and in these cases, patients may have been exposed germicides (formaldehyde, glutaraldehyde, and peracetic acid/hydrogen peroxide) that can elicit life-threatening reactions. The near abandonment of reuse in the United States makes these reactions rare.

Despite these changes to alternative sterilization methods and biocompatible dialysis membranes, reactions still occur and, in some cases, may be related to the dialysis membrane. PAN is a negatively charged synthetic membrane, which is composed of a copolymer of acrylonitrile and an aryl sulfonate. In the 1990s, severe anaphylactoid reactions were reported in patients dialyzed with PAN membranes who were also taking angiotensin-converting enzyme (ACE) inhibitors. Binding of Hageman factor XII to a negatively charged membrane leads to formation of kallikrein from prekallikrein and the subsequent release of kinins (i.e., bradykinin) from kininogen. Although cuprophane and polymethylmethacrylate membranes display an ability to activate factor XII, PAN activates it to a greater extent. Bradykinin, a molecule with a very short half-life, in turn activates production of prostaglandin and histamine release, with subsequent vasodilatation and increased vascular permeability. ACE inactivates bradykinin, and therefore ACE inhibitors can prolong the biological activities of bradykinin, which are highly calcium dependent. PAN membranes pretreated with positively charged polyethyleneimine are associated with markedly reduced bradykinin activation, although it is safer to simply use another dialysis membrane for these patients.

Several anaphylactoid reactions have also been reported in patients dialyzed with bleach reprocessed polysulfone membranes and treated with ACE inhibitors. These reactions ceased once the use of bleach was discontinued. Furthermore, a cluster of anaphylactoid reactions was reported in patients dialyzed with different membranes (acrylonitrile 69) who were also taking ACE inhibitors. Hydrogen peroxide/peracetic acid was the reprocessing agent used, and the reactions abated once reprocessing was discontinued, despite continued use of ACE inhibitors.

Recently case series of patients developing acute reactions to dialysis membranes of the polyarylsulfone family (polysulfone, polyethersulfone) have been reported. Typically, patients developed symptoms within the first 30 minutes of dialysis (dyspnea, hypotension, hypoxia, bronchospasm, chest pain, urticaria, and pruritus). Reactions in half of the patients occurred in the first week after starting dialysis with the membrane and in many cases after the first contact. However, another half of patients developed reactions at variable times after exposure (range 1 to 36 months). A careful analysis of these reactions could not isolate the sterilization method, housing materials, or potting materials as causes. Instead, the reactions appeared to be isolated to the type of membrane material. Importantly, 85% of these patients also reacted to other dialysis membranes of the same chemical family, and thus the use of alternative membranes (PAN, substituted cellulose, or polymethylmethacrylate) is needed for these patients. These cases highlight the continued vigilance that is needed for patients undergoing HD and that despite changes in technology, reactions to dialysis membranes still occur.

Although reuse and reprocessing of dialysis membranes has decreased substantially, it is important to realize that disinfectants such as hypochlorite (bleach) and formaldehyde can lead to serious reactions. These reactions generally abate when the dialyzer is thoroughly rinsed before use.

Reactions Associated With Drugs and Other Exposures

During a dialysis session, patients may receive numerous medications that include drugs given with each dialysis treatment (heparin, erythropoietin, iron compounds) as well as drugs given on a more sporadic nature for specific indications (antibiotics). Clinicians must be aware that patients can develop reactions to these medications and should carefully review medication administration records in any patient developing a reaction.

Patients undergoing HD are exposed to repeated heparin doses, which have been associated with several forms of allergic reactions. Heparin-induced thrombocytopenia (HIT) is a well-described entity and discussed later in this chapter. However, it is important to note several reports of HIT-associated anaphylactoid reactions in HD patients that occur 5 to 30 minutes after intravenous or subcutaneous administration of either unfractionated heparin (UFH) or low-molecular-weight heparins (LMWH). Clinical features include abrupt falls in platelet counts (consistent with HIT), hypotension or hypertension, wheezing, dyspnea, and cardiovascular collapse associated with the presence of anti-platelet factor (PF) 4/heparin antibodies. In addition, both UFH and LMWH have been linked to episodes of typical anaphylaxis during HD. An outbreak of UFH-associated anaphylactic episodes occurred in 2007–2008 and was traced to a lot of heparin produced in China that was contaminated with oversulfated chondroitin sulfate (OSCS). It is not clear if low-level contamination with OSCS is associated with other anaphylactic reactions to heparin seen outside of these cases. A further complicating issue is that heparin “allergy” in an HD patient can also be caused by preservatives in the heparin preparation such as paraoxybenzoic esters.

IgE-mediated allergies to the constituent proteins of natural rubber latex are well known and can occur in HD patients. One study found sensitization to natural rubber latex in 1.1% of nonatopic chronic HD patients. Latex-specific IgE and positive skin testing to latex can help identify these patients, and treatment requires the use of alternative elastomers such as polyvinylchloride, nitrile, or polyurethane. Other potential allergic exposures include washing solutions, chlorhexidine, and other environmental allergens.

The majority of dialysis patients are exposed to repeated doses of intravenous (IV) iron compounds that can be associated with a range of adverse reactions, including severe, life-threatening events. The prevalence of hypersensitivity reactions to IV iron preparations is very low (comparable to the safest radiocontrast agents at 0.01% to 0.1%). There is ongoing debate as to whether certain IV iron preparations are safer than others, and with the exception of higher-molecular-weight iron dextran compounds, which are associated with a higher rate and increased severity of reactions, all other compounds appear similar in their safety profile. Of note, high-molecular-weight iron dextrans are no longer available in the United States. Mechanistically, IV irons reactions do not appear to be IgE mediated and are likely nonimmune in nature. One hypothesis is that IV iron preparations, in susceptible patients, activate the complement system, leading to the formation of anaphylatoxins (C3a, C5a), which can further stimulate mast cells to release vasoactive mediators, leading to the clinical expression of a hypersensitivity reaction. Reactions to IV iron preparations can range from minor symptoms such as pruritus, flushing, arthralgias, and myalgias to more significant symptoms such as chest pain, persistent hypotension, shortness of breath, and cardiovascular collapse. The European Medicines Agency Committee for Medicinal Products for Human Use has issued recommendations for the management of the risk for reactions to IV iron. These recommendations include (1) informing patients of the risk for a reaction; (2) the need for close observation of patients receiving IV iron for any reactions during and for at least 30 minutes after the infusion; and (3) training of staff to recognize and treat reactions, including ready access to resuscitation medications if needed. There is no utility to the practice of using a test dose of IV iron to predict the likelihood of a reaction, and this practice has been largely abandoned. Instead, caution is warranted with all IV iron dosages even if previous dosages have been well tolerated.

Treatment options to manage reactions to IV iron preparations depend on the severity of the reaction. Mild reactions (itching, back/joint pains, flushing) can be managed by stopping the infusion and monitoring the patient. If the symptoms improve, the infusion can be restarted with caution. Moderate reactions (cough, chest tightness, shortness of breath, hypotension) are treated with immediate cessation of the infusion as well as administration of IV fluids and corticosteroids. Severe and life-threatening reactions (wheezing, stridor, cyanosis, persistent hypotension) are treated with a combination of IV epinephrine, fluids, and corticosteroids. In patients who have had life-threatening reactions to IV iron compounds, it is safest to avoid all further IV iron infusions. For patients who may be at higher risk for drug reactions, such as highly atopic individuals, premedication with IV corticosteroids can be considered.

Approach to the Dialysis Patient With a Reaction

All patients suspected of having a reaction during a HD session should be approached as having a potentially life-threatening event ( Fig. 26.1 ). Given the complexity of the dialysis procedure, a rapid assessment of the patient as well as a review of the dialysis session and any medication administered must occur as a first step. Because the symptoms of a reaction are nonspecific and include cardiovascular collapse, a rapid determination of possible dialysis-related factors such as hemolysis, air embolism, or a pyrogenic reaction (PR) should be assessed (see later) before determining that the patient may be suffering from either a dialyzer- or medication-related event. Furthermore, the dialysis procedure should be halted immediately and blood should not be returned to the patient. For those patients with signs and symptoms of anaphylaxis, rapid administration of subcutaneous epinephrine, IV corticosteroids, and antihistamines (H ₁ and H ₂ antagonists) should occur along with respiratory support if needed. The maximum initial dose of epinephrine is 0.2 to 0.5 mg in adults and can be given subcutaneously or intramuscularly. Epinephrine should not be administered intravenously unless there is life-threatening shock. The dose of epinephrine can be repeated after 5 minutes if there is no improvement. An inhaled β2-agonist can be added for those patients with bronchospasm. Milder reactions may be treated with corticosteroids and antihistamines or simply monitored closely.

Approach to the patient with a reaction while undergoing hemodialysis.

Identification of the offending agent is critical in secondary prevention but may be difficult given the number of potential exposures. Depending on the mechanism of reaction, diagnostic methods that can aid in the identification of the reactive agent include skin tests, specific serum IgE quantification, serum tryptase levels, lymphocyte transformation, and basophil activation assays and in vivo challenge testing. Consultation with an allergy specialist may be helpful in challenging cases.

Complications Associated With Microbiological Contamination

Naturally occurring water bacteria commonly found in HD water systems include gram-negative bacteria (GNB) such as Pseudomonas species and nontuberculous mycobacteria. GNB release endotoxin or lipopolysaccharide (LPS) and other bacterial products, and nontuberculous mycobacteria are highly resistant to germicides. Several factors that are operative during dialysis place patients at risk for exposure to bacteria and/or bacterial products, including contaminated water or bicarbonate dialysate, improperly sterilized dialyzers, and cannulation of infected catheters, grafts, or fistulas. The bacteriological quality of treated water and dialysate remains an important issue, and many units report substandard results. The most widely accepted standards for water purity are those recommended by the Association for the Advancement of Medical Instrumentation (AAMI) and the European Pharmacopeia, which respectively allow bacterial growth of <200 colony forming units (CFU)/mL and <100 CFU/mL and an endotoxin concentration of <2 international units (IU)/mL and <0.25 IU/mL. However, a number of multicenter studies have reported that 7% to 35% of water samples have bacterial growth of >200 CFU/mL and up to 44% have endotoxin levels of >5 IU/mL.

Bicarbonate-containing solutions are highly susceptible to bacterial contamination. If stored for too long, sodium bicarbonate breaks down to sodium carbonate, which, along with glucose contained in the dialysate, constitutes a growth medium for bacteria. When GNB reach excessively high concentrations in the dialysate, serious health risks to patients, including PRs with or without bacteremia, can result. Indeed, outbreaks of clusters of infection in HD patients have been ascribed to bacterial contamination, which can occur at multiple places along the HD circuit, including the dialysate, carbon filters, inadequate disinfection, and other sources. For example, in 2007 several patients in a dialysis unit in San Jose, California, developed bacteremia as a result of an unusual GNB, a Halomonas species. Tracing back from the dialysis machine, the investigation determined that contamination of the bicarbonate solution was the root cause.

The passage of endotoxin from the dialysate into the blood can occur by diffusion or convection. The use of high-flux dialyzers increases the risk for passage of endotoxin, particularly lipid A (∼2000 Da), the active moiety of LPS, from dialysate into blood. LPS interacts with plasma LPS binding protein and mediates cytokine production by interacting with the monocyte CD14 receptor. The subsequent release of pyrogenic cytokines such as interleukin 1 and tumor necrosis factor produce a transient febrile reaction that may be associated with rigors and hypotension. Of note, another source of endotoxin or bacterial infection is intradialytic hypotension (IDH), which can cause transient mesenteric ischemia that may be sufficient to damage the GI mucosa and lead to bacterial and/or LPS translocation.

PRs should be entertained after septicemia has been ruled out. Careful examination of the dialysis access is warranted, and blood cultures should be obtained. Treatment of PR includes antipyretics, empiric broad-spectrum antibiotics, discontinuation of ultrafiltration whenever hypotension is present, and selective hospitalization. An outbreak of bacteremia among several patients involving a similar organism should prompt thorough search for bacterial contaminants of the dialysis equipment. Similarly, an outbreak of PRs should also prompt investigation of the dialysis circuit and water treatment facilities.

The prevention of PRs starts with strict adherence to the AAMI standards. In addition, the Centers for Disease Control and Prevention Division of Healthcare Quality Promotion and the Healthcare Infection Control Practices Advisory Committee have specific guidelines for environmental infection control that should be meticulously followed. In an era of high-flux dialysis and hemodiafiltration, some experts believe that these recommendations are too liberal and that sterile-pyrogen–free dialysis fluids (ultrapure dialysate) with bacteria < 0.1 CFU/mL and endotoxin < 0.03 EU/mL should be used. However, data to widely support this practice in HD are not yet available, even though many dialysis units have adopted this practice in the hope of decreasing chronic inflammatory stimuli.

Muscle Cramps

Muscle cramps are defined as prolonged and painful involuntary skeletal muscle contractions. For patients undergoing chronic HD, they are a common occurrence that has been reported in as many as 33% to 86% of treatments and can lead to shortening of HD treatments, failure to reach target weight, and significant impairments in quality of life. Despite this being a common and debilitating condition, there is little research to guide our understanding of the pathophysiology, optimal therapy, and prevention of muscle cramps. Speculation is that muscle cramps may be related to a combination of significant plasma volume contraction, changes in serum osmolality (progressive hypoosmolality), and contributions from deficiencies in magnesium, L-carnitine, vitamin C, and vitamin E. Muscle cramps typically occur near the end of the HD session and most often involve the muscles of the lower extremity, but any muscle may be affected. In terms of the dialysis prescription, lower dialysate sodium levels and higher ultrafiltration rates appear to be risk factors for the development of muscle cramps.

In the past, acute muscle cramps were managed by increasing the plasma osmolality with the administration of hypertonic saline, mannitol, or concentrated (50%) dextrose solutions given intravenously. These therapies are rarely used today given concerns that they may induce thirst and volume overload and limit the ability to get the patient to their target weight. Acute management often includes transiently slowing or stopping ultrafiltration as well as intradialytic massage and stretching of the affected muscle groups. For those patients who develop hypotension along with muscle cramps, prompt attention to raising blood pressure (slowing or stopping ultrafiltration, slowing blood flow rate (BFR), placing the patient in Trendelenburg position, and even administration of midodrine) should be the first course of action.

Preventing or reducing the frequency of muscle cramps during HD should be attempted in patients with frequent intradialytic symptoms. Several strategies have had variable efficacy. For patients who seem to develop muscle cramps associated with the need for high ultrafiltration rates (such as greater than 10 to 13 mL/kg/h), minimizing interdialytic weight gains is critical but often difficult to achieve. Minimizing episodes of IDH by various strategies such as sequential ultrafiltration/dialysis and the use of sodium modeling (such as starting from a dialysate sodium concentration of 145 to 155 mEq/L and decreasing linearly, exponentially, or stepwise to 135 to 140 mEq/L) may also be effective in some patients. It also may be reasonable to empirically increase the target weight by 0.5 kg to see if this lowers the frequency of muscle cramps. Higher dialysate sodium levels or oral salt loading may also ameliorate the frequency of muscle cramps but come at the expense of increased thirst and risk for higher interdialytic fluid gains. Despite very limited data, quinine has been used for the prevention of muscle cramps, perhaps by decreasing the excitability of the muscle endplate. However, the US Food and Drug Administration (FDA) has warned that the use of quinine for the prevention of dialysis-associated muscle cramps is not justified and is associated with severe adverse reactions, including cardiac arrhythmias, allergic reactions, and thrombotic thrombocytopenic purpura–hemolytic uremic syndrome, and thus should not be used. L-carnitine supplementation (administered intravenously [20 mg/kg] after HD or orally [330 mg two to three times per day]) in those patients with low levels may decrease the frequency of muscle cramps, but the data in support of its use are weak. Vitamin E supplementation has also had variable efficacy in decreasing the frequency of muscle cramps in several small trials. In one study the combination of both vitamin E and C was more effective in reducing cramp frequency than either alone. In another study, 400 IU of vitamin E reduced the frequency of muscle cramps by 68%. It is thus reasonable to try vitamin E in those patients with frequent muscle cramps. There are very limited data on a variety of other therapies that have been attempted to decrease the frequency of muscle cramps, including the use of gabapentin, short-acting benzodiazepines, and phenytoin.

Headache

Headache is a common complaint in HD patients, occurring with an incidence ranging from 27% to 73%. Dialysis-related headaches are defined as those starting or changing their characteristics (such as worsening) when the dialysis treatment starts. Headaches characteristically begin within 1 to 2 hours after initiating dialysis and are variously described as throbbing in nature, moderate in intensity, and most often in the frontotemporal region. Often the headache may worsen when the patient reclines, and when severe, it may be accompanied by nausea and vomiting. The headache often, but not always, resolves within 48 to 72 hours after dialysis. Many of these patients will have a history of preexisting headaches and may also have headaches in the interdialytic period, which can confound the diagnosis and therapy. In fact, one study noted that only 6.7% of headaches in the HD population were purely related to the HD session, highlighting the high prevalence of other headaches in these patients.

Although the pathophysiology of dialysis-related headache is not fully defined, certain risk factors are associated with its development. Patients who develop headache typically have lower magnesium levels both pre- and postdialysis, greater intradialytic decreases in serum urea levels, larger changes in body weight during HD sessions, and higher predialysis systolic and diastolic blood pressures. Low magnesium levels may be particularly important because this has been reported to potentiate vasospasm and vasoconstriction as well as modulating inflammation and the N-methyl-D-aspartate glutamate receptor associated with nociceptive transmission. Rapid changes in serum osmolality that occur early in the HD session as blood urea and solute levels decrease lead to translocation of water across the blood–brain (hematoencephalic) barrier (because cerebral concentrations of these solutes are stable over the first part of the HD session and an osmotic gradient favoring water movement into the brain occurs). This movement of water into the brain leads to increases in intracranial pressure along with symptoms of headache. In essence, headache may be a milder form of the dialysis disequilibrium syndrome (DDS) (discussed later). Both hypertension and hypotension during the dialysis procedure may also contribute to the development of headache. One study also reported correlations of dialysis headache with higher levels of calcitonin gene–related peptide and substance P. Some have also hypothesized that increases in nitric oxide and bradykinin during the HD session may be headache inducers. One intriguing but unproven hypothesis is that intradialytic removal of caffeine may precipitate headache. Lastly, headache may also be a somatic complaint in patients with depression, and this should be considered in HD patients, where the prevalence of depression is high.

Little data are available to guide the management of dialysis-related headaches, and general management principles are followed: oral analgesics (acetaminophen), magnesium supplementation for those patients with low levels, avoidance of large blood pressure and weight changes, and avoidance of caffeine overuse. In some patients, a reduction in the BFR early in the HD session may be helpful.

Dialysis Disequilibrium Syndrome (DDS)

DDS is defined as neurological deterioration occurring during HD and more typically occurring in patients during or immediately after their first treatment. DDS can be encountered in both acute and chronic kidney failure, and risk factors include high predialysis blood urea nitrogen levels (>175 mg/dL), a rapid fall in blood urea nitrogen levels with HD, preexisting neurological conditions, hyponatremia, and liver disease. The symptoms are nonspecific and mimic those occurring with increased intracranial pressure (such as with acute severe hyponatremia), such as restlessness, headache, nausea, vomiting, hypertension, mental confusion, obtundation, seizures, and coma. Thus a careful assessment of patients presenting with these symptoms should include other causes, such as subdural hematoma, acute cerebrovascular events including intracranial hemorrhage, hypoglycemia, and hypotension. Brain imaging (either computed tomography or magnetic resonance imaging) may reveal cerebral edema in patients with DDS. Although the syndrome is seen less common now than in the past (in part as a result of starting patients on HD with lower blood urea nitrogen levels and using lower blood and dialysate flow rates for the initial sessions), it is still encountered and needs to be recognized.

Although the pathophysiology is not completely known, it is felt that the primary factor is development of cerebral edema and increased intracranial pressure that is driven by water movement into brain cells and the interstitium by an osmotic gradient as a result of rapid falls in serum urea and other effective osmoles (the reverse urea hypothesis). Supporting this concept is the finding that measurement of urea in the blood and cerebrospinal fluid (CSF) indicated that after HD treatment there was a substantial gradient, with the urea concentration in the CSF being higher than that in the blood, and that this gradient caused water to move into the central nervous system, leading to rises in intracranial pressure. The magnitude of the CSF–to–plasma blood urea nitrogen gradient can be as high as 2 immediately after dialysis. Some have also argued that an increase in intracellular brain solutes (idiogenic osmoles), such as myoinositol, glutamine, and taurine, occurs with rapid HD and may also contribute to the osmotic disequilibrium between the CNS and vascular compartments. More recent data supporting the role of the reverse urea hypothesis are that in a rat model of advanced chronic kidney disease there was a decrease in urea transporters as well as an increase in aquaporin channels in brain cells. The consequence of these molecular changes may be a delayed exit of urea from astrocytes, as well as facilitation of water transport into cells by the increase in aquaporin channels.

Prevention of DDS focuses on minimizing the osmotic gradient that leads to water entering the CNS. Various techniques have been used in this regard. No controlled trials are available to guide therapy, and thus clinical judgment on the rate of urea reduction must factor in individual patient characteristics such as the predialysis blood urea nitrogen level, history of neurological disease, and other risk factors. A reasonable goal for a first dialysis session is a reduction in the blood urea concentration of 40% (urea reduction ratio of 0.4). To achieve this goal, the first HD session should be limited to 2 to 2.5 hours and the blood flow should be 200 to 250 mL/h. In addition, the use of hemofiltration (convective solute removal), as opposed to HD, which does not result in as large a solute gradient, may mitigate the risk for DDS. Similarly, in those at the highest risk for DDS (such as those with acute kidney injury and traumatic brain injury or an intracranial hemorrhage), continuous renal replacement therapy with slow urea removal should be considered. The other strategy used to prevent DDS is to raise the osmolality of the intravascular compartment during HD to decrease the osmotic gradient and lessen the risk for cerebral edema. The easiest way to achieve this is to increase the concentration of sodium in the dialysate and use sodium modeling. Studies with this approach have found that higher dialysate sodium concentrations were associated with amelioration of DDS as well as a decrease in electroencephalogram abnormalities compared with standard sodium dialysate. Other osmotic agents such as mannitol and glucose have also been successfully used in the prevention of DDS.

Treatment of DDS, once established, centers on rapidly reducing intracranial pressure by raising blood osmolality with mannitol or hypertonic saline. Even with these maneuvers, patients may not recover, and this highlights the critical importance of prevention of DDS.

Restless Legs Syndrome

Restless legs syndrome (RLS) is characterized by an uncomfortable and urgent need to move the limbs (usually the lower extremities) and typically begins or worsens during periods of rest or inactivity. The International Restless Legs Syndrome Study Group has developed specific diagnostic and severity criteria, and these include the feature that the symptoms are at least partially relieved by movement or stretching. ESRD patients have a much higher prevalence rate of RLS than the general population, reaching approximately 30%. Although the precise pathophysiology of RLS is not well understood, disturbances in dopaminergic neuronal transmission as well reduction in iron stores in specific brain regions are thought to be important, and these insights inform therapeutic maneuvers. Uremic toxicity is also thought to be important because the majority of patients recover from RLS after kidney transplantation. Importantly, RLS may manifest itself during the HD session (likely because of inactivity during these 3 to 4 hours), and up to 20% of patients undergoing HD prematurely terminate a dialysis session secondary to the sensory and motor symptoms of RLS.

Studies have found that RLS negatively affects the quality of life for HD patients, with significant negative effects on sleep quality and quantity and a higher prevalence of depression and anxiety. Interestingly, RLS is also associated with a higher risk for cardiovascular disease, and this may, in part, be mediated by augmentation of sympathetic nervous system activity. Thus it is not surprising that RLS in ESRD patients is a marker for higher mortality rates and lower survival.

Treatment of RLS in ESRD patients is challenging, and there are very few clinical trials available to guide practice. The first-line pharmacological therapy for RLS is a dopamine agonist such as ropinirole or pramipexole ( Table 26.1 ). Several small clinical trials have reported that these agents can decrease RLS symptoms by approximately 70%. Side effects with these agents can include nausea, vomiting, and nightmares. The anticonvulsant gabapentin has also had efficacy and is approved by the FDA for the treatment of RLS. Iron supplementation has also had variable but transient efficacy for RLS, and patients should be treated with IV iron as per protocols used to treat anemia. Intradialytic exercise training is also effective and has been reported to improve sleep quality and decrease RLS symptoms during the HD session.

Seizures

There are numerous potential causes of seizures in the patient undergoing dialysis ( Table 26.2 ). It is important to know the patient’s history and medication use, and details of the dialysis session, because this information will often yield significant clues as to the cause of the seizure. A rapid physical examination looking for any focal neurological deficits should be performed because this may suggest an intracranial process. Patients who are just initiating HD may develop a seizure as a result of DDS or from severe electrolyte disturbances such as hyponatremia or hypocalcemia. Erythropoietin, especially in higher doses, had been associated with the development of hypertensive encephalopathy and seizures in as many as 2% to 17% of patients. However, the contemporary use of much lower doses of erythropoietin, as well as more aggressive control of blood pressure, has made erythropoietin-associated seizures an uncommon occurrence.

Changes in blood pressure (either acute lowering or elevations) can be associated with seizures, especially in patients with predisposing conditions. IDH should be avoided in these patients. Hypertensive encephalopathy can manifest as headaches, vomiting, confusion, and seizures and can be encountered when the patient presents for dialysis or even during the dialysis session. Proper treatment focuses on controlled decreases in blood pressure, which should be closely monitored in an intensive care unit (ICU) setting.

Numerous electrolyte abnormalities can be associated with seizures, which are usually of the generalized tonic-clonic type. In most cases, rapid changes in electrolyte levels are more likely to precipitate seizures than chronic changes. These include hypocalcemia, hyponatremia, and hypomagnesemia. Rapid recognition and treatment of these disorders can be lifesaving. For instance, for patients with severe hyponatremia, small increases in the serum sodium of 5 mEq/L can be enough to reduce cerebral edema and halt seizure activity. This can be achieved with 100 mL boluses (up to three times) of 3% saline given intravenously.

Patients with a history of seizures and taking chronic antiepileptic medications may pose special challenges in the HD unit. This is due to the fact that ESRD and dialysis alter the distribution, metabolism, and clearance of many antiepileptic drugs. Some medications, such as levetiracetam, phenobarbital, and primidone, are removed by dialysis and thus require supplementation or careful timing of administration to avoid lowering therapeutic levels and precipitating “breakthrough” seizures. Other drugs, such as phenytoin, carbamazepine, and sodium valproate, are poorly dialyzed and do not require supplementation. In all cases, antiepileptic drug levels should be monitored closely.

Aluminum neurotoxicity is largely of historic interest and seldom seen today. The fall in incidence is due to improved water treatment and the avoidance of aluminum-containing phosphate binders. Those few patients who may manifest symptoms of aluminum neurotoxicity, which includes impaired memory, myoclonic jerks, and other neurological symptoms, have generally been on HD for many years and may have received repeated courses of aluminum-containing phosphate binders. Plasma aluminum levels are elevated in these cases.

Treatment of established seizures requires cessation of dialysis, maintenance of airway patency, and investigation for metabolic abnormalities. Phenytoin and intravenous diazepam or clonazepam may be required. Intravenous administration of 50% dextrose in water should be administered if hypoglycemia is suspected.

Other Neurological Complications

Visual loss is rare during HD and may be caused by central retinal vein occlusion, precipitation of acute glaucoma (because of changes in osmolality), ischemic optic neuropathy associated with IDH, or Purtscher-like retinopathy caused by leukoembolization. Patients experiencing visual changes during HD should have their treatment stopped immediately and be referred for an emergent ophthalmology examination.

Intradialytic Hypotension

IDH occurs in an estimated 8% to 20% of dialysis sessions. Complicating the evaluation are the variable definitions of IDH. Various studies use a systolic blood pressure (SBP) or mean arterial pressure cutoff (often <90 mmHg SBP), whereas others include only symptomatic episodes. IDH appears to be due to a complex interplay of factors including total volume and rate of fluid removal, rate of intravascular space “refill,” degree of osmolar changes between fluid compartments, and impaired compensatory mechanisms caused by underlying medical conditions and/or medications. Symptomatic episodes may include mental status changes such as syncope or seizure in severe cases, nausea, muscle cramping, and end-organ ischemia-related symptoms, among many other manifestations. Even asymptomatic patients may suffer from silent cardiac stunning and cerebral ischemia.

IDH has been associated with a number of negative clinical outcomes, including increased rates of access thrombosis, cardiac remodeling, and higher 1- and 5-year mortality. A number of predisposing risk factors have been studied. These include shorter treatment times, higher ultrafiltration rates, higher dialysis dose, left ventricular hypertrophy, diabetes, longer dialysis vintage, higher dialysate temperatures, and dialysis after the “long break” (longer interdialytic interval), among others.

Strategies to prevent or ameliorate IDH revolve around reducing intradialytic weight gain through patient education, optimizing and limiting ultrafiltration volume and rates during dialysis sessions, lessening the effect of osmolar changes, and increasing vascular tone and/or venous return. Dietary sodium intake is a significant driver of interdialytic fluid gains. As such, patient counseling should include a focus on reducing sodium intake as possible. Once in-center, reducing ultrafiltration volumes and rates via increased total dialysis time or additional sessions may reduce IDH. Various biofeedback technologies to monitor blood volume or heart rate variability have been trialed to optimize ultrafiltration during treatment with varying degrees of success. A high-sodium bath has been used to decrease osmolar-driven fluid shifts and reduce IDH; however, this may lead to significant sodium transfer and higher interdialytic weight gains. A recent metaanalysis suggested that stepwise sodium profiling reduces IDH compared with conventional dialysis and linear sodium profile methods. Thus a dialysis program that uses stepwise sodium profiling with a neutral net sodium transfer may be preferable. Cooled dialysate has been found to have multiple benefits: reduced left ventricular remodeling, reduced brain white matter disease, and lessened IDH. The stabilization of core temperature may reduce the reflexive vasodilation from overheating during later stages of dialysis, yielding stable systemic vascular resistance. Cooling may also be the mechanism of reduced IDH seen in online hemodiafiltration because increased thermal energy loss from the circuit yields an unintended method of cooling. Lastly, the selective α ₁ receptor agonist midodrine has been found generally safe but variably effective for treatment of IDH.

Other strategies have shown promise in smaller studies and include arginine vasopressin infusion; hypertonic saline administration; modification of dialysate calcium, bicarbonate, and magnesium; L-carnitine administration, and use of pneumatic compression devices.

Intradialytic Hypertension

Hypertension in dialysis patients is generally driven by extracellular volume excess. Patients with intradialytic hypertension however, experience paradoxical increases in blood pressure despite ultrafiltration and presumed adequate volume removal. When defined as an increase in systolic pressures of >10 mmHg over the course of treatment, intradialytic hypertension occurs in 12% to 13% of prevalent patients. The pathophysiology varies by patient but is likely multifactorial, including activation of the renin-angiotensin-aldosterone and sympathetic nervous systems, decreased arterial compliance, and increased endothelin 1 production/endothelial cell dysfunction. Removal of dialyzable antihypertensive medications may also play a role. In addition, subclinical volume overload and increased peripheral resistance may also be causative. A study by Van Buren et al. evaluated the role of extracellular water (ECW) at end treatment and found that patients with IDH completed dialysis with higher ratios of ECW to total body water and with increased total peripheral resistance compared with controls.

In those predisposed to intradialytic hypertension, ambulatory blood pressure monitoring has indicated that elevated blood pressure lasts for hours posttreatment. Poor clinical outcomes have been associated with intradialytic hypertension, specifically higher mortality. Despite the prevalence of intradialytic hypertension and potential mortality risk, agreed-on treatment strategies remain opinion based. Given the possible role of subclinical volume overload, it seems reasonable to perform serial target weight challenges on hypertensive dialysis patients and consider longer or additional sessions more than thrice weekly. The Frequent Hemodialysis Network trial reported improved blood pressure control, with lowered target weights and decreased total number of medications. Carvedilol has shown promise in reducing the number of episodes of intradialytic hypertension, possibly through blockage of endothelin 1. Other suggestions include use of less-dialyzable antihypertensives, reducing use of erythropoietin-stimulating agents (ESAs), and lowering dialysate sodium.

Arrhythmias

Arrhythmias, both atrial and ventricular, are a common occurrence in HD patients. Atrial fibrillation is present in 22% of patients, and ventricular arrhythmias occur in another 8% per US Renal Data System (USRDS) data. Lethal arrhythmias are the leading cause of death among patients with ESRD. Dialysis patients have a high burden of cardiovascular disease that predisposes them to arrhythmias, including valvular heart disease, atherosclerotic heart disease, and congestive heart failure—the last two occurring in about 45% of patients. Dialysis-specific risk factors include rapid electrolyte (especially potassium) shifts during dialysis, increased sympathetic tone during treatment, uremia, and myocardial stunning.

Despite the potential mortality, large prospective studies of arrhythmias have not occurred. Two recent trials of implantable cardiac loop monitors in Australian and Brazilian dialysis patients reported that the vast majority of “stable” dialysis patients experience transient arrhythmias and often more than one type. In the Brazilian study, most arrhythmias were clinically silent and supraventricular tachycardia predominated. In the Australian group, atrial fibrillation accounted for 62% of transient arrhythmias. Concerning was that both studies had large numbers of patients with ventricular arrhythmias. A study of US patients with loop recorders is currently underway. Management of atrial fibrillation with anticoagulation remains controversial. Some retrospective studies suggest benefit, although a recent metaanalysis reported no mortality benefit and even potential harm. Novel oral anticoagulants such as apixaban have not been well studied in ESRD.

Strategies to reduce the risk for arrhythmias in dialysis patients are mostly opinion based. Most authors advocate reducing electrolyte shifts during dialysis by slowly correcting derangements and avoiding large changes in electrolyte levels. Other strategies include use of antihypertensives that decrease sympathetic tone, such as beta blockers, ACE inhibitors, and aldosterone receptor blockers, and treating underlying cardiac conditions.

Sudden Cardiac Death

Sudden cardiac death (SCD) is the leading cause of death among dialysis patients, accounting for approximately 29% of all deaths. The period of highest risk is in the second month after initiating dialysis. In the general population, SCD is most often associated with coronary artery disease and ventricular arrhythmias. The mechanism in dialysis patients has been presumed to be lethal ventricular arrhythmias. More recently, devices such as implantable cardiac defibrillators and loop recorders have shown bradycardia terminating in asystole as the most common disturbance implicated in SCD. Several studies have found the highest-risk period for SCD is near the end of the “long break”—the 72-hour span in usual thrice weekly dialysis. An earlier study reported clustering of SCD in the 12 hours after dialysis after the long break and a second peak in the 48- to 60-hour period after the final dialysis session in a week. This has led to speculation that the stress of the procedure itself is a risk factor for SCD, as well as the metabolic derangements seen from >48 hours between sessions. Other characteristics associated with SCD in the dialysis population include use of low potassium, magnesium, and calcium baths; underlying structural heart disease; diabetes; use of high doses of ESA, use of vitamin D analogs, excessive heart rate variability, high ultrafiltration rates, and prolonged QTc interval.

There are no large prospective randomized trials indicating benefit of a particular intervention for reducing SCD. The use of implantable cardiac defibrillators remains controversial. A small pilot trial of a wearable defibrillator in dialysis patients has found benefit. A recent retrospective trial compared an ESRD implantable cardioverter defibrillator (ICD) recipient cohort with a propensity-matched ESRD non-ICD cohort and found no benefit. A larger prospective study is underway to determine the utility of wearable cardiac defibrillators in incident patients as primary prevention. Medication therapy also remains uncertain. Carvedilol has been found to reduce mortality in a small trial of dialysis patients with reduced left ventricular function, though the reduction in death from SCD was not statistically significant. Given the characteristics of the dialysis procedure itself associated with SCD, it seems prudent to avoid using very low potassium and calcium baths. Ultrafiltration rates should be minimized by increasing time or additional sessions when necessary. Avoiding the components of the long break that may contribute to increases in SCD, such as high volume fluid intake and electrolyte shifts, should be accomplished through counseling if possible.

Finally, management of a cardiac arrest in the dialysis unit should follow the American Heart Association guidelines emphasizing consistent chest compressions. Automated external defibrillators are recommended by the National Kidney Foundation Kidney Disease Outcomes Quality Initiative and present in most dialysis units but have not yet produced improved outcomes. Procedural causes of SCD, such as massive air embolism, acute hemolysis, or errors in dialysate composition, are specific to dialysis and should be managed accordingly when found.

Myocardial Stunning

Myocardial stunning, defined here as transient development of segmental wall motion abnormalities with ventricular dysfunction, has been estimated to occur in 27% to 64% of patients during dialysis. Although IDH may accompany these episodes, more often they are clinically silent. Myocardial stunning has also been associated with higher 1-year mortality. The pathophysiology is thought to be decreased coronary artery perfusion, which has been established using various noninvasive imaging modalities, including intradialytic positron emission scans and magnetic resonance imaging. Predisposing factors for myocardial stunning include a history of left ventricular systolic dysfunction, male sex, higher left ventricular mass index, increased age, and higher ultrafiltration rates.

Repetitive myocardial stunning may also predispose to development of permanent segmental abnormalities. This has given rise to the concept of a “vicious cycle” of recurrent ischemia and ensuing cardiac remodeling ( Fig. 26.2 ). The deleterious effects of repetitive myocardial stunning have also been proposed as the potential underlying cause for the higher mortality in patients with high ultrafiltration rates. The mortality link found in patients with ultrafiltration rates >10 mL/kg/h has been significant enough that an ultrafiltration rate quality measure has recently been added to the ESRD Quality Incentive Program (QIP) in the United States.

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