Primary Care Reports March 10, 1997

Navigating the Treacherous Waters of End-Stage Renal Disease

Author: Walter G. Belleza, MD, Department of Emergency Medicine, University of Maryland Medical System, Baltimore, MD.

Editor: Larry B. Mellick, MD, Chief of Service and Chairman, Director of Pediatric Emergency Medicine and Department of Emergency Medicine, Medical College of Georgia, Augusta, GA.

Peer Reviewers: Norman Peterson, MD, Professor of Surgery and Urology, University of Colorado Health Sciences Center; Associate Director of Surgery and Urology Division Director, Denver Health Medical Center, Denver, CO.

Robert A. Schwab, MD, Associate Professor, Department of Emergency Medicine, University of Missouri at Kansas City School of Medicine, Kansas City, MO.

Editor’s Note—The patient with end-stage renal disease (ESRD) is a diagnostic and therapeutic challenge for the primary care physician. Clinical presentations range from the nearly asymptomatic patient with laboratory evidence of mild hyperkalemia to the patient with fulminate pulmonary edema or cardiac arrest. Within a narrow window of time, the physician must initiate potentially treacherous therapeutic maneuvers for a patient functioning within narrow metabolic boundaries.

By definition, ESRD occurs when a patient’s kidneys can no longer sustain life without the aid of dialysis therapy or a renal transplant. It is at the end point of chronic renal failure where the majority of clinical complications occur. Chronic renal failure (CRF) implies that an irreversible reduction in renal function exists, and recovery of that function is unlikely.

Nearly every organ system suffers in ESRD. If profound enough and not treated accordingly, ESRD results in the uremic syndrome. The uremic syndrome is a constellation of multisystemic complications that result from the accumulation of nitrogenous wastes and metabolic by-products. Symptoms may range from fluid overload and congestive heart failure to encephalopathy and coma. To prevent this and other systemic derangements, patients are started on either peritoneal dialysis or hemodialysis. Dialysis therapy can be life-saving but can also cause its own complications. In this issue, the author reviews the complex constellation of problems associated with ESRD.

Demographics

An estimation of the number of patients suffering from ESRD is provided by the United States Renal Data Systems (USRDS). Current worldwide estimates indicate a gradual increase in the number of patients entering dialysis therapy, with the United States having the highest rate.1 As of 1993, statistics from USRDS demonstrate that more than 220,000 patients suffer from ESRD, with an annual growth rate of 8-9%.2 Some projections indicate that the number of dialysis enrollees will exceed 250,000 by the year 2000.4 The increase in numbers may also be due to more diabetic and elderly patients being accepted for dialysis therapy. In addition, there is a growing population of patients with predialysis renal insufficiency who may require treatment. As of 1990, this group was estimated to number between 648,000 and 708,000 patients.5

In the United States, the most common causes of chronic renal failure, in decreasing incidence, are: diabetes, hypertension, glomerulonephritis, cystic renal disease, and interstitial nephritis.6 A disproportionate number of patients with ESRD are young, urban-dwelling blacks who suffer from severe, untreated hypertension.1,4

Pathophysiology

After receiving a pathogenic insult, the kidney can either recover and continue to function normally, develop chronic renal insufficiency, or progress to ESRD. Factors that influence disease progression include the severity and type of the primary insult, presence of other chronic diseases (hypertension, diabetes, HIV), age, and continuing insult (infection, obstruction). Once chronic renal insufficiency is established, and plasma creatinine exceeds 1.5-2.0 mg/dL, progression to ESRD occurs with an almost linear decline in the glomerular filtration rate (GFR).7 Although the aforementioned exogenous factors can serve to accelerate functional decline, disease progression still occurs in their absence. This is due to many intrinsic processes that are poorly understood.

If the original insult results in irreversible injury, the remaining functional glomerular units become hyperperfused. This results in increases in glomerular capillary pressure that become injurious by inducing histological changes that cause glomerular hypertrophy, fusion of epithelial foot processes, and mesangial expansion.7-9 The mesangial expansion causes the eventual collapse of the capillary lumens and the eventual appearance of patchy glomerulosclerosis.

In addition to causing cellular changes, this hyperfunction induces an "injury response" that involves cellular elements, chemical mediators, and biologically active compounds and results in glomerular and tubulointerstitial damage. Implicated cellular elements include macrophages, monocytes, leukocytes, and platelets.8,9 Once attracted to the damaged area, these elements help initiate an inflammatory cascade involving chemical mediators such as interleukin-1, platelet activating factor, thromboxane A2, and heparinase.8,9 The chemical mediator interleukin-1 promotes attachment of inflammatory cells such as neutrophils and monocytes and stimulates the release of thromboxane A2. Thromboxane A2 serves as a vasoconstrictor that decreases glomerular perfusion and promotes platelet aggregation. Platelets, in turn, release platelet-derived growth factor that promotes growth of fibroblasts and proliferation of smooth muscle cells and the release of prostaglandins and leukotrienes that perpetuate the inflammatory cascade.

Clinical Effects

Cardiovascular Complications. Cardiovascular and cerebrovascular complications account for 15-30% of deaths in patients suffering from chronic renal failure.19-22 Although not considered an independent risk factor for heart disease, chronic renal failure may coexist with other proven cardiac risk factors, such as diabetes, hypertension, and hypercholesterolemia. In addition, ESRD makes control of these conditions more difficult. Cardiovascular conditions that are likely to require emergent evaluation and treatment are hypertension, congestive heart failure (CHF) or pulmonary edema, myocardial ischemia, pericardial disease, and dysrhythmias.

Hypertension. Hypertension in the patient with chronic renal failure is a multifactorial problem. Secondary complications of renal failure, such as volume overload, sodium imbalance, elevated catecholamine levels, and derangements in the renin-angiotensin system, can be superimposed on a pre-existing hypertensive condition.23,24 A hypertensive emergency exists when signs of severe progressive end-organ damage (e.g., encephalopathy, CHF, cardiac ischemia) occur in the presence of elevated blood pressure. Although a hypertensive emergency does not usually occur until the diastolic blood pressure exceeds 130 mmHg, it can occur at levels as low as 110 mmHg.

Congestive Heart Failure/Pulmonary Edema. As with other complications in renal failure, CHF involves multiple pathophysiologic mechanisms. In addition to primary cardiac dysfunction, volume overload, positive sodium balance, high output failure from anemia, and arteriovenous fistulas are major contributing factors. Cardiac dysfunction can result from hypertension, left ventricular hypertrophy, cardiac ischemia, cardiomyopathy, electrolyte abnormalities, dysrhythmias, and hyperparathyroidism.21,23,24,26-28 Although the most common cause of CHF and pulmonary edema in patients with ESRD is volume overload, all of the previously mentioned factors can cause heart failure and should be considered in the differential diagnosis. Volume overload may range between 5-10 L and can result from a seemingly innocuous ingestion of food or fluid.

Pericardial Disease. Prior to widespread dialysis therapy, pericarditis occurred in more than 50% of ESRD patients and was a harbinger of early demise. However, the current incidence is between 2%-19% and can occur in patients not receiving dialysis as well as those undergoing dialysis.35 In patients not receiving dialysis, its presence indicates the need to initiate therapy. In patients currently on dialysis, pericarditis indicates the presence of stresses such as trauma and infection or the need for a more aggressive dialysis regimen. The exact pathophysiologic process in under-dialyzed patients is unknown but is thought to be secondary to retained metabolic by-products.

The most common chief complaint is substernal, nonexertional, sharp pleuritic chest pain. The pain can increase by moving, yawning, and lying supine. It is relieved by sitting upright and can predate diagnostic evidence by 1-2 weeks. Other complaints include shortness of breath, cough, weight loss, fever, and malaise. Clues that indicate significant effusion are new dysrhythmias, frequent episodes of hypotension during dialysis, or a decreasing need to medically control hypertension in a previously hypertensive patient.23

Dysrhythmia. Coronary artery disease (CAD), cardiac dysfunction, electrolyte disorders, and the use of potentially proarrhythmic medication are common occurrences in patients with ESRD.14,39,40 These factors, along with pericardial disease, decreased oxygen delivery from chronic anemia, and dialysis-induced hypotension, can predispose patients to dysrhythmias. Common dysrhythmias include atrial fibrillation and flutter, PVCs, and non-sustained ventricular tachycardia.41-44 Dysrhythmias may be precipitated by any condition that impairs cardiac oxygen delivery, and electrolyte disorders such as hyperkalemia, hypercalcemia, and hypermagnesemia.

Coronary Artery Disease. CAD and myocardial ischemia commonly occur in patients with ESRD.19-22,43 The presence of left ventricular hypertrophy, an AV fistula, and fluid overload may increase cardiac oxygen demand, while chronic anemia can decrease oxygen availability. It was previously thought that the incidence of myocardial ischemia was more prevalent among patients with renal failure and ESRD. Recent studies have shown that, when adjustments are made for age and coexisting disease, there is no significant difference between this population and others. The differential diagnosis of chest pain should include pericarditis, pleural effusion, aortic dissection, pneumothorax, infection, and pulmonary embolism.

Acute Neurologic Complications. Neurologic dysfunction is a well-known consequence of ESRD and can involve the central and peripheral nervous systems.65,66 Complications range from neuropathies and the restless leg syndrome to lethargy and coma. The challenge for the physician is to distinguish between acute, chronic, and potentially life-threatening disorders. Two significant problems that may be seen are the dialysis disequilibrium syndrome and mental status changes.

Dialysis Disequilibrium Syndrome. This well-known complication usually occurs during or shortly after dialysis. Neurologic symptoms include headache, weakness, restlessness, confusion, seizures, and coma. The syndrome results when the removal of solutes from the blood is too rapid to allow an equilibration between the central nervous system and the rest of the body.24,48 It occurs more frequently in patients who have more severe metabolic derangements prior to dialysis and in those undergoing a more aggressive dialysis regimen. The syndrome is a diagnosis of exclusion, and other etiologies, such as infection, CVA, uremic encephalopathy, hypoxia, subdural hematoma, and drug intoxication, should be considered.

Altered Mental Status. The list of problems that can cause mental-status change in patients with ESRD is extensive. (See Table 1.) In addition to common conditions such as stroke, medication effects, and hypoglycemia, complications from the dialysis process must be considered. These include hypotension, the disequilibrium syndrome, dysrhythmia, and spontaneous CNS hemorrhage.63 Acute onset may indicate cerebrovascular accidents, dysrhythmias, or trauma. A history of slow onset and dialysis noncompliance may indicate uremic encephalopathy.

Hematological Complications. Bleeding and anemia are common occurrences in patients with ESRD. In addition to an underlying platelet dysfunction, bleeding can occur secondary to concurrent heparin administration during dialysis. Anemia can be a consequence of ESRD but can result from an acute hemorrhagic episode. The challenge for the physician is to identify the acuity of these conditions and initiate appropriate therapy.

Common sites of bleeding include vascular access sites and the gastrointestinal tract.72 Spontaneous hemorrhage into the subdural, retropharyngeal, and retroperitoneal spaces can also occur.12,61-63 Any area of progressive swelling and pain may harbor occult hemorrhage.

Infectious Complications. Infection is the second most common cause of mortality and morbidity in patients with ESRD and accounts for 15-40% of deaths in this population.26,46 In addition to compromised humoral and cellular immune responses, patients often have indwelling peritoneal or vascular access devices that serve as ports of entry for infectious agents.47,48 Conditions that may act as immunosuppressants are chronic uremia, malnutrition, iron overload from transfusion, and electrolyte disorders. Areas such as the urinary tract and lungs have diminished local defenses, making them more susceptible to infection. Other contributing factors to urinary infection include bladder stasis, dysmotility, and underlying structural disease. Complaints of dysuria and frequency may be absent because of decreased urinary flow.

The patient with ESRD should be viewed as an immunocompromised host. Because of this, the presence of fever should prompt an extensive evaluation. Patients may present with fever, chills, hypothermia, joint pain, constitutional complaints, and symptoms referable to the site of infection. Common sites of infection include the lung, urinary tract, vascular access sites, and the peritoneum. Vascular access sites and peritoneal catheters are the most common sources of infection in patients undergoing hemodialysis and peritoneal dialysis, respectively.50- 52

Electrolyte Complications. Electrolyte abnormalities are the hallmark of chronic renal failure. While many of these complications are not life-threatening and respond to hemodialysis, hyperkalemia, hypercalcemia, and hypermagnesemia can result in clinical decompensation if not treated. These conditions are rare in the compliant and adequately dialyzed patient but can occur due to dietary indiscretion and dialysis noncompliance.

Hyperkalemia. Causes of hyperkalemia include pharmacological agents, dietary and dialysis noncompliance, rhabdomyolysis, metabolic acidosis, and catabolic states. Medications that produce hyperkalemia include: nonselective beta blockers, calcium channel blockers, succinylcholine, and digoxin if taken in toxic doses.54,55 Tissue breakdown from rhabdomyolysis results in release of intracellular potassium. Extracellular potassium shifts occur with metabolic acidosis.

There are no specific clinical or physical manifestations that can aid in early diagnosis of hyperkalemia. Because clinical presentation can range from cardiac arrest to mild constitutional symptoms, a high index of suspicion for this problem should be maintained in any patient with ESRD. Although most patients are asymptomatic, the most common complaint is weakness.34 Because the most important consequence of hyperkalemia is increased cardiac irritability, an ECG should be obtained early.

Hypercalcemia and Hypermagnesemia. Hypercalcemia and hypermagnesemia by themselves, or in conjunction with hyperkalemia, can increase cardiac irritability and potentiate cardiac dysrhythmias. Though not a common consequence of renal failure, hypercalcemia and hypermagnesemia can occur due to the inadvertent use of common medications—phosphate binders, vitamin D analogues, and calcium supplements in hypercalcemia, and magnesium-containing antacids and lithium therapy in hypermagnesemia. As in hyperkalemia, patients often present with a variety of clinical complaints that range from weakness and malaise to cardiopulmonary instability and coma.

Patients with mild hypercalcemia are often asymptomatic but generally have clinical signs once the level exceeds 11.5 mg/dL. Presentation may include nausea, vomiting, fatigue, muscle weakness, and abdominal pain. Mental status changes, such as lack of concentration, confusion, and coma may also occur.24 Although most physical findings are nonspecific, signs of long-standing hypercalcemia such as band keratopathy may be present.

Hypermagnesemia inhibits the presynaptic release of acetylcholine and norepinephrine. Although most side effects involve neural tissue, magnesium also affects vascular smooth muscle and cardiac tissue. Nausea and vomiting can occur at levels of 4-5 mEq/L (2.0-2.5 mmol/L), loss of deep tendon reflexes and mental status changes occur at levels of 4-7 mEq/L (2.0-3.5 mmol/L), and respiratory paralysis occurs at levels of 10-15 mEq/L (5.0-7.5 mmol/L). Other signs include hypotension, lethargy, and paralysis.

Emergent Complications of Dialysis Therapy

The objective of dialysis therapy is the removal of toxins, metabolic waste products, and excess volume from the vascular space. Through the processes of ultrafiltration and diffusion, solutes and material pass from the vascular space to a dialysate solution by crossing semipermeable membranes located either intraperitoneally (peritoneal dialysis) or externally (hemodialysis). By adjusting the duration of therapy and the nature of the dialysate material, specific changes can be made in the constitution of a patient’s plasma. Although many complications can occur from dialysis therapy, those likely to require emergent evaluation involve instability during the dialysis process, mechanical defects, and infection. Because unique problems occur in peritoneal dialysis and hemodialysis, they will be discussed separately.

Peritoneal Dialysis. Peritoneal dialysis involves the sterile introduction of dialysate fluid into the peritoneum through a surgically implanted catheter. The dialysate fluid is then allowed to equilibrate with the patient’s plasma for a specific amount of time (dwell time). By adjusting the dialysate material and the length of dwell time, the consistency of a patient’s plasma can be adjusted. The fluid is later withdrawn under sterile conditions. Although multiple modalities of peritoneal dialysis are available, the one most commonly used is continuous ambulatory peritoneal dialysis (CAPD). In this modality, the dwell time lasts from 4-6 hours and treatment is performed by the patient four times daily. Because of its ease of use, avoidance of hemodynamic instability from rapid volume shifts, and freedom from use of a dialysis center, CAPD is favored by younger patients, the elderly, and those with severe cardiovascular problems. Because CAPD is relatively stable, conditions such as hypotension, chest pain, and neurological deficits should not be attributed to the dialysis process.

Mechanical Complications. Mechanical complications include obstruction and leakage from the catheter site. Patients will notice either an inability to infuse or properly remove dialysate fluid. This can be due to kinking of the catheter tubing, intraperitoneal migration, or obstruction from overlying omentum or peritoneal debris.59

Infection. Infection is the most common complication that afflicts the patient receiving peritoneal dialysis, and it occurs an average of once every nine months.30 In addition to diffuse abdominal pain and dialysate fluid that becomes cloudy, infected peritoneal dialysis patients may experience nausea, vomiting, fevers, and chills. The most common infectious agents are skin-inhabiting Staphylococcus epidermidis and Staphylococcus aureus.46,50,67 Infection is usually due to a break in aseptic technique during dialysis exchange. Other organisms include gram-negative organisms such as Escherichia coli, Pseudomonas, Enterobacter, and fungal species such as Candida.46,50,67

In addition to microbial infection, peritonitis can occur secondary to allergic reactions to the dialysis catheters (eosinophilic peritonitis ) or dialysate fluid (sclerosing peritonitis). While eosinophilic peritonitis is a self-limited condition, sclerosing peritonitis may result in abdominal adhesions that require discontinuation of peritoneal dialysis. If adhesions are severe, surgical lysis may be required.

Hemodialysis. Hemodialysis involves exchanges between a patient’s plasma and a dialysate bath through semipermeable membranes. Vascular access is achieved either through a temporary large intravenous double lumen catheter or repeated cannulation of a permanent, surgically constructed, arterio-venous fistula. Fistula construction uses either native or animal vasculature or synthetic material. The fistula usually connects the patient’s radial artery to a large vein in the patient’s nondominant arm in an end-to-side or side-to-side fashion. Complications involve mechanical obstruction, infection, hemorrhage, and hemodynamic instability during or after dialysis therapy.

Mechanical Complications. The most common mechanical problem with vascular access devices is obstruction from thrombosis, which is usually caused by venous hyperplasia at the venous end of the graft’s anastomotic site. Thrombosis can also result from trauma, inadvertent compression while sleeping, or during compression of a graft hemorrhage. Mechanical obstruction may result from inadvertent kinking of the graft site. The likelihood of obstruction is increased following dialysis from a combination of a low-flow state and hypercoaguable condition.30,68 Obstruction can also occur in temporary double lumen devices.

History may reveal a loss of the bruit or thrill at the fistula site. If obstruction of a double lumen occurs, severe extremity edema can result. Temporary devices may be inadvertently or intentionally removed with resultant hemorrhage.

Infection. The most common source of infection in patients undergoing hemodialysis treatment is the access site. In addition to symptoms of a localized process, infection of access sites can cause metastatic infection involving the vertebrae, joints, and cardiac valves.34 Joints commonly infected include the wrist, knee, and shoulder. The aortic valve is most frequently infected from metastatic infections. As in peritoneal dialysis, gram-positive skin flora such as S. aureus and S. epidermidis are the usual causative agents. Infection usually results from frequent handling and cannulation as well as breaks in aseptic technique.

Although localized warmth, tenderness, and erythema may indicate infection, their absence does not exclude the possibility of infection. In fact, as many as one-third of patients will have no localizing signs and may only complain of constitutional symptoms such as malaise, fever, chills, nausea, and vomiting.23,30

Hemorrhage. Bleeding is a common problem with vascular access sites. This is due to frequent cannulation, platelet dysfunction, and use of heparin during dialysis. Unlike "natural grafts," the walls of synthetic devices cannot collapse and are more prone to hemorrhage and formation of pseudoaneurysm. A pseudo-aneurysm is a pulsatile hematoma with a pseudocapsule, while an aneurysm is a true expansion of the vessel wall. Both can produce hemorrhagic complications. An additional cause of bleeding is the AV fistula or graft that is used prematurely prior to adequate maturation after implantation.

Hemodynamic Instability. Hypotension commonly occurs during dialysis and is usually due to a combination of underlying autonomic dysfunction and decreased cardiac output from acute depletion in intravascular volume. The decrease in vascular volume occurs from fluid removal in patients who enter dialysis either euvolemic or relatively hypovolemic. Other possibilities include: cardiac dysfunction from ischemia, arrhythmia, or pericardial effusion, infection, sepsis, antihypertensive use, pulmonary embolism, air embolism, and anaphylaxis. Anaphylaxis can occur at the initiation of dialysis treatment and may be a reaction to the dialyzer membrane, the sterilizer used in cleaning the dialysis machine, or bacterial endotoxins.63 Dialysis personnel should provide records that document the time of occurrence, any coexisting symptoms, and any diagnostic or therapeutic measures.

Air Embolism. Air embolism is a rare but potentially lethal complication of dialysis therapy that results from passage of air from either an external mechanical malfunction in the circuit or from the dialyzer itself. The dialyzer may be a source of air if refrigerated dialysate containing dissolved air is used.

Clinical presentation depends on the amount of air introduced and the position that the patient is in at the time. Although complications can result from as little as 5 mL of air, larger amounts are required to produce cardiovascular collapse. If the patient is upright, a rushing sensation to the head may soon be followed by neurological dysfunction. Patients lying supine may complain of chest pain or shortness of breath. Those in the Trendelenburg position are fortunate because air will pass into the lower extremities, sparing the heart but demonstrating patchy cyanosis on the lower extremities.

Prehospital Care

Initial prehospital support emphasizes the ABCs with initiation of any required resuscitative measures per pre-established ACLS protocols and rapid transport to an appropriate institution. If an airway is required, EMS personnel should be aware that patients with ESRD can have clotting dysfunction and that tracheal intubation may result in inadvertent hemorrhage.10-12 If the patient can breathe spontaneously, the sitting position may be helpful. Oxygen should be administered via high-flow delivery systems. Efforts to obtain peripheral IV access should be made but should not delay transport. Field attempts at cannulation of vascular grafts should be avoided. Although pharmacologic therapy is limited in the field, early measures include the use of furosemide (Lasix) and nitroglycerin if congestive heart failure is suspected. Nitroglycerin also addresses cardiac ischemia.

Pre-hospital caregivers should attempt to obtain historical information from the patient and family members. Aside from the past medical history, helpful information includes length, frequency, compliance, and duration of any dialysis and medical treatments, previous renal complications, prescription and non-prescription drug use, and any illicit drug use.

Emergency Care

General Resuscitative Measures. Patient status must be assessed quickly and stabilized prior to initiating any diagnostic evaluation. As with any medical emergency, the ABCs (airway, breathing, circulation) consistently take precedence. In addition to stabilization measures, patients should be placed on a cardiac monitor and continuous pulse oximeter, receive an ECG, and have appropriate laboratory studies obtained shortly after arrival. If hemorrhage is suspected, blood should be sent for type and crossmatch.

Airway. The patient with ESRD can develop respiratory distress from conditions that afflict the general population (pneumonia, myocardial infarction, pulmonary embolism) and those that occur with increasing frequency among dialysis patients (volume overload, cardiac/pleural effusion).

The airway can be secured by a variety of measures, including nasotracheal or oral intubation. If mechanical ventilation is chosen, extreme care should be taken to avoid traumatic intubation. Patients with ESRD may have a severe bleeding diathesis and may bleed spontaneously into the retropharyngeal space.10-12 Although succinylcholine can cause hyperkalemia, its use is not contraindicated in patients with ESRD unless severe hyperkalemia is suspected as the cause of compromise.13,14 Vecuronium (Norcuron) may also be used, but pancuronium should be avoided in patients with glomerular filtration rate (GFR) less than 10 mL/min because of possible recurarization after initial recovery.

Breathing. Once the airway has been secured, adequate oxygenation should be administered via high-flow oxygen or by mechanical means. A possible option is the use of continuous positive airway pressure (CPAP) techniques. CPAP’s efficacy in avoiding intubation in patients with pulmonary edema secondary to cardiac dysfunction and fluid overload from ESRD has been shown in several studies.14-18

Circulation. To avoid any complications with vascular graft cannulation, peripheral access is ideal. If this is not possible, or if intravascular monitoring is required, central venous access should be obtained. If neither of these can be done and IV access is needed quickly, the vascular graft can be cannulated as a last resort. (See Table 2.)

Diagnostic Evaluation. History/Physical. As with any other medical problem, treatment begins with a thorough history and physical examination. Information should be obtained from the patient, family members, other physicians, and dialysis center personnel. The history should ideally seek to establish the patient’s baseline functional and medical status; the duration, etiology, and any complications from ESRD; and the level of compliance with dialysis, medical, and dietary therapy.

Evaluation of cardiovascular complications such as myocardial ischemia, dysrhythmias, and hypertensive crisis should be approached in the same manner as in those patients with normal renal function. The physical exam must include a thorough cardiopulmonary, cerebrovascular, and neurological evaluation. Signs of volume overload must be sought in patients with congestive heart failure. Complaints of chest pain should prompt consideration of aortic dissection and pericarditis as well as cardiac ischemia. Signs of aortic dissection may include a new diastolic murmur and pulse/pressure differentials in the extremities.

The evaluation of pericarditis can be difficult because physical findings such as the pericardial friction rub may not be audible until well after the onset of symptoms.35 The rub is best auscultated along the left sternal border at the third and fourth intercostal spaces using the diaphragm of the stethoscope. It can have a one-, two-, or three-component character, and its presence along with pain is highly suggestive of pericarditis.36 The presence of pulsus paradoxus, a decrease in systolic blood pressure greater than 10 mmHg during inspiration, should raise suspicion of significant pericardial effusion.

The patient with ESRD should be viewed as an immunocompromised host, and nonspecific complaints as well as fever should prompt consideration of infection. Significant information includes the duration of symptoms, focal complaints, previous infectious complications, HIV status, recent hospitalizations, vaccination status, any recent dental or medical instrumentation, and any illicit drug use. If the patient is sexually active, a social history with an emphasis on high-risk behavior is important. If the patient is receiving dialysis, the time and occurrence of any fever should be sought. Fever that occurs early in dialysis or shortly after cessation is usually secondary to infection. If fever occurs during dialysis, a "pyrogen" reaction may be causative.

The physical exam must include close inspection of the likely infectious sites, such as the lung, urinary tract, peritoneum, and catheter access sites. If the patient is diabetic, the oropharynx, integument, and extremities should be carefully inspected. A cardiopulmonary exam should focus on any new murmurs, signs of pulmonary consolidation, and manifestations of embolic disease. If the patient has fever and abdominal pain signs of other intra-abdominal processes, such as pancreatitis, appendicitis, cholecystitis, or mesenteric ischemia, an abscess must be sought before the diagnosis of CAPD peritonitis is made. Sexually active patients should receive a thorough pelvic and rectal exam. Joints should be checked for metastatic infection if a vascular graft is infected.

If patients are receiving peritoneal dialysis or hemodialysis, catheter and vascular access sites should be closely examined for erythema, fluctuance, discharge, and tenderness. As mentioned previously, an alarming one-third of patients with vascular access infections will manifest no symptoms.23,30,50 If a vascular shunt is used, its functional integrity should be established. Loss of the bruit or thrill may indicate occlusion. Signs of aneurysm or pseudoaneurysm may include pain, thinning of the overlying skin, exposure of graft material, or impingement of adjacent structures. Aneurysms are a common nidus of infection and may "seed" distant sites, such as the joints, vertebrae, and cardiac valves.

Diagnostic Studies. Because nonspecific complaints may indicate a serious condition, initial diagnostic studies should include at least a 12-lead ECG, electrolytes, and cardiac monitoring. If clinically indicated, a CBC, coagulation studies, ABG, chest x-ray, blood cultures, urinalysis, lumbar puncture, therapeutic drug levels, and toxicology screen should be obtained. It should be noted that patients undergoing hemodialysis can demonstrate low leukocyte counts following dialysis, and, because of impaired cellular response, may not show the expected "left shift" of immature forms in the setting of infection.

The 12-lead ECG is an important tool because it may detect subtle changes secondary to pericardial disease, electrolyte disorders, and ischemia. Early ECG changes in pericarditis include diffuse ST segment elevations with a concave upward contour as well as PR segment depression. Later, the ST segments may return to baseline. The T wave amplitude may decrease and eventually invert in those leads that had ST segment elevation.73 However, ECG diagnosis can be complicated by the presence of baseline ST-T wave changes often present in this population. ECG evidence of tamponade includes widespread decreases in QRS voltage and electrical alternans. Electrical alternans refers to changing levels of QRS voltage heights in an ECG that occurs when the heart changes position because of its suspension in a fluid-filled pericardium.

Electrolyte disorders such as hyperkalemia, hypercalcemia, and hypermagnesemia may produce characteristic ECG changes. The ECG changes found in hyperkalemia may not correlate with the level of elevation.

In hypercalcemia, a decreased QT interval is the most reliable ECG change and usually occurs at levels greater than 13 mg/dL.7 Additional changes include prolongation of the PR interval and QRS complex, increased QRS voltage, and T-wave flattening.7 At higher levels, atrioventricular block can progress to complete heart block. Hypermagnesemia may demonstrate bradycardia, heart block, and asystole. Morphologic changes include prolongation of the PR, QRS, and QT intervals.

Interpretation of chest radiographs may be difficult. Chronic volume overload may make radiographic diagnosis of pneumonia difficult if prior films are not available for comparison.

If peritonitis is suspected in patients receiving CAPD, at least 150 cc of peritoneal fluid should be obtained. Peritoneal fluid should be grossly examined for color and character and sent for Gram’s stain, cell count, and culture. Peritonitis is diagnosed by the presence of a white cell count greater than 100 cells/mm3 with a predominance of polymorphonuclear cells.67 If a predominance of eosinophils or mononuclear cells is found, diagnoses of eosinophilic peritonitis or tubercles peritonitis, respectively, should be considered. Although a Gram’s stain exam has a low predictive value, it may help in the early diagnosis of fungal peritonitis. Blood cultures are usually negative in peritonitis.

Additional studies may include a CT scan for suspected intracranial processes or an echocardiogram for suspected pericardial effusion or tamponade.

Specific Treatment Modalities

Hypertensive Complications. Hypertensive complications in patients with ESRD are usually due to volume overload or medical noncompliance. The ideal treatment for hypertensive emergencies caused by volume overload is dialysis. If emergent dialysis is unavailable, parenteral therapy should be started.

The treatment goal in a hypertensive emergency is to reduce the blood pressure in a rapid and controlled fashion. Reasonable goals are to reduce the blood pressure by 20-30% or to a level of 160/100 mmHg in the first 24 hours.7,23 If a cerebrovascular accident is suspected, drastic reduction should be avoided and a mean arterial pressure (MAP) maintained at a level of 120-160 mmHg to insure adequate cerebral perfusion.7,25

If signs of hypertensive crisis exist, parenteral therapy using nitroprusside at an initial dose of 0.3 mcg/kg/min is the drug of choice. It acts as both an alpha- and beta-adrenergic blocker and can reduce both cardiac preload and afterload. Potential thiocynate toxicity can be avoided by limiting infusion to less than 48 hours, initiating early dialysis, and maintaining levels between 5 and 10 mg/dL.

If nitroprusside is unavailable, nitroglycerin may be used and is a safe and effective venodilator. If immediate intravenous access is unavailable, nitroglycerin can be given sublingually every five minutes x 3 with blood pressure checked frequently. Subsequently, nitroglycerin can be infused intravenously at an initial rate of 5 mcg/min.

Other potentially useful agents include combination alpha- and beta-blockers (IV labetalol), diuretics, IV ACE inhibitors, and calcium-channel blockers. 100 mL of 30% sorbitol given orally or rectally may be used if the hypertensive condition exists in the presence of pulmonary edema. It acts by creating an osmotic gradient between the gastrointestinal tract and the vascular space.

Congestive Heart Failure/Pulmonary Edema. The most common exacerbating factor causing congestive heart failure in patients with ESRD is volume overload, but other factors to consider are cardiac ischemia, dysrhythmia, hypertensive emergency, and medication/dialysis noncompliance. The first goal of treatment is to ensure hemodynamic stability. Presence of cardiogenic shock may require infusion of vasopressor agents such as dopamine or inotropes such as dobutamine. If anemia is suspected of causing high-output failure or contributing to myocardial ischemia, infusion of packed red cells should be considered. Central venous pressure monitoring may be required with these modalities to avoid volume overload.

Hemodialysis or peritoneal dialysis are the preferred methods of removing excess volume. Because lack of immediate availability may limit their use in some centers, pharmacotherapy should be used as a temporizing measure.

Safe and effective agents immediately available include nitroglycerin, morphine sulfate, and furosemide.30-33 These agents act by reducing cardiac preload through venodilation. Nitroglycerin 0.4 mg SL q 5 can be given initially and followed by an IV drip started at 5 mcg/min titrated to effect while avoiding hypotension. Morphine 2-5 mg IV decreases preload and decreases patient anxiety. Frequent dosing should be avoided to prevent respiratory depression. Though ineffective in initiating diuresis in an anuric patient, furosemide 80-120 mg IV can cause venodilation with consequent decreases in left ventricular filling pressures and pulmonary capillary wedge pressures.33

Additional agents include nitroprusside and sorbitol. Nitroprusside started at 0.3 mcg/kg/min acts as both a preload and afterload reducer, thereby decreasing left ventricular pressure and cardiac oxygen demand; 100 mL of 30% sorbitol given orally or rectally promotes an osmotic shift between the vascular space and the gut.7,34 Its late onset of action (1-6 hours) and copious diarrhea may make management difficult. Phlebotomy should be avoided.

Pericardial Disease. The patient’s hemodynamic status will dictate the therapeutic approach to pericarditis or pericardial tamponade. (See Figure 1.) If the patient is hemodynamically stable, exacerbating factors such as trauma, infection, dialysis non-compliance, and medications should be identified and corrected. The patient’s nephrologist should be informed, and arrangements should be made to either initiate dialysis or intensify the patient’s current regimen. If the patient is complaining of pain or fever, indomethacin or steroids may be used for relief once other sources of fever and chest pain have been ruled out.

If the patient is hemodynamically unstable, the patient should be prepared for pericardiocentesis. Because of potential complications such as myocardial laceration, dysrhythmia, iatrogenic tamponade and hepatic laceration, pericardiocentesis should be deferred for those patients in shock.38 If the patient is mildly unstable but responds to volume expansion with saline or mannitol, immediate surgical consultation should be made and the patient prepared for either pericardiotomy or pericardiectomy.

Dysrhythmias. Treatment of specific dysrhythmias should follow currently recommended guidelines, with specific dose adjustment. If cardiac arrest exists, hyperkalemia should be suspected and 10-20 mL of 10% calcium chloride or 15-20 mL of 10% calcium gluconate should be given over 10-15 minutes. Calcium should be avoided if digitalis toxicity is suspected, as it may worsen the dysrhythmia. The only ACLS protocol drug to avoid is bretylium. If ischemia is suspected, treatment should include aspirin, nitrates, heparin, and possible thrombolytics.

Cardiac Ischemia. There is no significant alteration in the management of myocardial infarction and ischemia in patients suffering from chronic renal failure and ESRD.

Aspirin, nitrates, heparin, and thrombolytics should be used according to currently established guidelines. Because underlying anemia impairs oxygen delivery, transfusion with packed red blood cells should be considered. Hemodialysis should be avoided during this period.

Infections

General Considerations. Specific treatment regimens are based on likely foci of infection and the patient’s underlying renal function. In the unstable septic patient, cultures should be obtained and vancomycin 1g IV and gentamycin 1.7 mg/kg started empirically. This regimen provides coverage for the likely gram-positive and gram-negative organisms that commonly infect this population. Diabetics, patients with HIV, and those suspected of nosocomial pathogens require therapy tailored to likely pathogens, local resistance patterns, and any previous culture results.

Pneumonia is a common source of infection, and the most likely agent is streptococcal pneumonia. If recent hospitalization has occurred, infection with gram-negative and nosocomial pathogens should be suspected, and antibiotics should be chosen accordingly. If the patient is extremely ill, infection with gram-negative organisms, Staphylococcus, and Legionella should be suspected. Tuberculosis should also be considered, especially among groups at higher risk, such as the institutionalized, the poor, and those with HIV.53

If a urinary source is suspected, the physician should consider whether the patient suffers from polycystic kidney disease. These patients require lipid-soluble antibiotics (clindamycin, chloramphenicol, trimethoprim/sulfamethoxazole) and surgical consultation if intra-renal or perinephric abscesses are suspected.

Peritonitis. Care of peritoneal dialysis patients with peritonitis should include quick dialysate exchange (which helps alleviate pain and remove peritoneal debris) and intravenous and intraperitoneal antibiotics. The initial antibiotics chosen should have anti-staphylococcal coverage. Additional considerations should be made for gram-negative organisms and methicillin-resistant strains of Staphylococcus.

Other therapeutic agents include heparin and rifampin. Heparin given intraperitoneally at a dose of 500 units/lL of dialysate for 3-5 days helps prevent obstruction of the catheter and prevents formation of fibrin that acts as a haven for microbial growth. Rifampin is usually administered for relapsing peritonitis. It acts by penetrating the bacterial protective sanctuaries of peritoneal cellular debris and the biofilm located in and around dialysate catheters. Fortunately, the majority of patients with peritonitis can be treated as outpatients if they are clinically stable, reliable, and able to maintain adequate nutrition. (See Table 3.)

Hospital admission is mandatory for patients who cannot maintain nutritional balance, who show signs of clinical instability, and are suspected of having either fungal or sclerosing peritonitis. Fungal peritonitis requires removal of the dialysis catheter, systemic antifungal therapy, and nutritional support. Sclerosing peritonitis requires removal of the catheter, discontinuation of peritoneal dialysis, and surgery for complications secondary to abdominal adhesions.

Vascular Access Infection. If access site infection is suspected, the patient’s nephrologist should be informed. Concerns of vascular access site aneurysms or thrombosis should lead to vascular surgery consultation as well. Initial treatment should be vancomycin 1g IV ´ 1, and gentamycin 1.7 mg/kg ´ 1 if gram-negative infection is suspected. The long half-life (5-7 days) and antimicrobial spectrum of these agents make them ideal agents for outpatient treatment. Patients with hemodynamic instability, graft compromise, or inability to maintain adequate nutrition require admission.

Electrolyte Disorders

Hyperkalemia. Treatment goals in hyperkalemia are to insure cardiac stability, facilitate translocation of extracellular potassium, and enhance excretion. The immediate goal in hyperkalemia is to stabilize the myocardium by administering 10% calcium chloride or 10% calcium gluconate. These agents should be given immediately to patients in cardiac arrest or to patients exhibiting signs of rhythm instability.

Following initial stabilization, agents that help translocate extracellular potassium should be administered. These include beta-agonists, IV insulin, and sodium bicarbonate.

Beta-agonists and insulin act by stimulating the cellular Na+K+ ATPase pump to translocate extracellular potassium.54,55,56 Albuterol, 20 mg in 4 mL NS given by nebulizer can lower potassium by 1.0 mmol/L and has few side effects. Ten to 20 units of regular insulin IV along with 50 cc of D50 can lower potassium levels by 0.6-1.0 mmol/L over one hour. Because hypoglycemia is a potential side effect, initial therapy should be followed by IV D5W.

The role of sodium bicarbonate is controversial. Some studies have not proven its efficacy, but current emergency medicine sources advocate its use. The dose is 50 mEq IV over 5-10 minute.7,57-60,71

The ideal means of potassium removal is dialysis, but its rapid availability limits its use. Sodium polystyrene sulfate (Kaexylate) can be given either orally or rectally and exchanges potassium for sodium using the gastrointestinal tract. Kaexylate 25 g/25 cc of 70% sorbitol orally, or 50 g/50 cc of 70% sorbitol rectally, removes 0.5-1.0 mmol of potassium for every gram of kaexylate. Sodium overload can result from Kaexylate treatment, so close monitoring is required.

Disposition. Patients who are symptomatic require admission to a monitored setting. Those having cardiovascular instability need an intensive care unit. Patients with mild elevations (5.5-6.0) who demonstrate no ECG manifestations and who are asymptomatic may receive conservative therapy (albuterol, insulin/glucose, and Kaexylate) and be discharged, if the patient’s nephrologist is notified and agrees. Such patients must be reliable, and hemodialysis must be arranged in a timely fashion. If compliance is in question, the patient should be admitted to ensure that dialysis takes place.

Hypercalcemia. Unlike patients with normal renal function, fluids and diuretics are ineffective in the treatment of hypercalcemic patients with ESRD. Those with levels between 12 mg/dL and 15 mg/dL can often await timely dialysis. Those with levels greater than 15 mg/dL require emergent treatment regardless of symptoms. This involves IV fluids if the patient’s volume is depleted, salmon calcitonin intravenously at 5 MRC U/kg q6hr, and prompt dialysis. Although the effects of steroids are delayed, their use should be considered.

Hypermagnesemia. Treatment goals are to ensure respiratory stabilization, cardiac stability, and magnesium elimination. Mechanical ventilation may be required if respiratory depression is significant. Ten mL of 10% calcium chloride or calcium gluconate IV should be given for cardiac instability and may be repeated twice every 5-20 minutes. Elimination is best achieved through hemodialysis.

Hematologic Complications

Spontaneous Hemorrhage. Treatment involves ensuring hemodynamic stability and preventing further hemorrhage. Resuscitative measures include direct pressure, establishing large-bore IV access, and infusion of crystalloid and/or packed red blood cells as appropriate. If compression is required at the dialysis catheter site, excessive pressure should be avoided to prevent occlusion of the catheter. Persistent bleeding may indicate the presence of an aneurysm or pseudoaneurysm. Tourniquet use above the vascular catheter should be avoided unless fulminate hemorrhage is present

Correction of suspected coagulopathy may require specific pharmacological therapy. If heparin is a suspected factor in major bleeding, protamine 0.5 mg/100 units of heparin used can be given. It is best given within 30 minutes of the last heparin dose. To correct platelet dysfunction, DDAVP, 0.3 mcg/kg in 50 cc of NS IV or 3 mcg/kg nasally can be administered.64 A subcutaneous dose of 0.4 mcg/kg can also be used, but absorption may be erratic. Ten bags of Cryoprecipitate can also be administered.11 Dialysis can help correct the bleeding diathesis, but its emergent use may be limited by lack of immediate availability.

Traumatic Hemorrhage. The patient with ESRD who is injured should be approached in the same fashion as other trauma victims. Resuscitation should follow standard ATLS protocols.

Volume resuscitation should use both crystalloid solutions and blood products as indicated. Because lactated ringer’s solution contains 4 mEq/L of potassium, it should be avoided because of its potential to cause hyperkalemia. Anemia is a common occurrence among patients with ESRD, and even minor blood loss may impair oxygen delivery; transfusion with packed red blood cells should be considered early. Crossmatching patients may be difficult due to the presence of red cell antibodies from previous transfusion.

Neurologic Complications

Altered Mental Status. In general, the evaluation and management of altered mental status in the patient with ESRD is the same as for other patients. A higher index of suspicion, however, should be maintained for spontaneous subdural hemorrhage. In addition, the dialysis disequilibrium syndrome should be kept as a diagnosis of exclusion. Treatment involves infusion of osmotically active fluid such as mannitol or hypertonic saline. The patient’s nephrologist should be consulted prior to initiating therapy.

If a seizure occurs or is suspected, there is no contraindication to using phenytoin, phenobarbital, or diazepam. Because of decreased protein binding, phenytoin should be loaded to achieve a level between 5-10 mcg/mL.

Dialysis-Associated Complications

Peritoneal Catheter Obstruction. Treatment should include manipulating the patient’s position in an attempt to relieve the obstruction. Definitive treatment using a trochar device and thrombolytic agents necessitates a surgical consultant.

Vascular Catheter Obstruction. Since it is difficult to differentiate between a mechanical and thrombotic obstruction, angiography must be performed promptly. Urokinase 2500- 5000 IU can be given if the obstruction is acute, and the vascular surgeon has been consulted. This should be done as soon as possible to preserve function.

If a double-lumen catheter device is obstructed, gentle aspiration may be corrective. Urokinase or streptokinase may also be given. Forceful irrigation must be avoided to prevent distal embolization.

Vascular Access Hemorrhage. Treatment of hemorrhage includes firm, nonocclusive pressure for 5-10 minutes and identification of any correctable bleeding disorder. Observation should continue for 1-2 hours to assure homeostasis. A vascular surgeon should be consulted if functional compromise, rapid expansion, or if imminent rupture is suspected. If rupture occurs, a tourniquet should be applied proximal to the site and resuscitative measures begun.

Air Embolism. If air embolism is suspected, all venous lines should be clamped immediately; the patient should be placed in the left lateral decubitus position and given 100% oxygen. This allows the air to be trapped at the apex of the right ventricle. If the patient develops air embolism while in Trendelenburg, he or she should be left in that position. If the patient is in arrest, percutaneous aspiration of air with an intracardiac needle is required. Additional treatments include IV corticosteroids for cerebral edema and heparin or low molecular weight dextran to improve microcirculation.

Dialysis-Induced Hypotension. Treatment should be tailored to the underlying condition. Most episodes of hypotension respond to volume infusion administered in the dialysis unit. If a patient presents with continuing instability despite early resuscitative measures, etiologies other than modest volume deficits must be investigated. To treat the hypotension, small aliquots of volume in 100-200 mL increments should be given with close monitoring. If a patient is mildly symptomatic and all underlying factors, such as arrhythmia, cardiac dysfunction, and infection, can be ruled out, the hypotension may be treated with food and fluids containing sodium.

Summary

The incidence of ESRD has been progressively increasing over the past two decades. Because of an increasing geriatric population and acceptance of patients with conditions such as severe hypertension, diabetes, and HIV into dialysis therapy, this trend will most likely continue. As a result, the primary care physician is increasingly likely to encounter the many potential complications of ESRD.

ESRD and its complications are difficult entities to manage in both the chronic and acute care settings. The problems that cause rapid decompensation of the ESRD patient involve cardiovascular conditions, infections, metabolic disorders, and complications secondary to dialysis therapy. Thorough knowledge is required if the primary care physician is to successfully evaluate and treat this complicated patient population.

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Physician CME Questions

22. Therapeutic approach to a patient with pericardial effusion or tamponade is based on:

a. the patient’s ECG changes such as electrical alternans.

b. the presence of pulsus paradoxus.

c. the patient’s hemodynamic status.

d. the results of the patient’s echocardiogram.

23. The only drug used in ACLS resuscitation that should be avoided in ESRD patients is:

a. procainamide.

b. beta-blocker agents.

c. lidocaine.

d. bretylium.

24. Treatment of choice in severe hypermagnesemia is:

a. sodium bicarbonate.

b. Kaexylate.

c. calcium chloride/calcium gluconate.

d. insulin with glucose.

25. Therapy for hemorrhage at the vascular access site includes:

a. thorough "packing" of the hemorrhagic site.

b. tourniquet use.

c. firm, nonocclusive compression for 30 minutes.

d. firm, nonocclusive compression followed by timely vascular surgical consultation.

26. Cardiovascular and cerebrovascular complications account for what percentage of deaths in patients suffering from chronic renal failure?

a. 95%

b. 15-30%

c. 75%

d. less than 5%