Pharmacotherapy A Pathophysiologic Approach, 9th Ed.

30. Hemodialysis and Peritoneal Dialysis

Kevin M. Sowinski, Mariann D. Churchwell, and Brian S. Decker


 Images Hemodialysis (HD) involves the perfusion of blood and dialysate on opposite sides of a semipermeable membrane. Solutes are removed from the blood by diffusion and convection. Excess plasma water is removed by ultrafiltration.

 Images Native arteriovenous (AV) fistulas are the preferred access for HD because of fewer complications and a longer survival rate. Venous catheters are plagued by complications such as infection and thrombosis and often deliver low blood flow rates.

 Images Adequacy of HD can be assessed by the Kt/V and urea reduction ratio (URR). The National Kidney Foundation’s Kidney Disease Outcomes Quality Initiative minimum goal Kt/V is greater than 1.2 per treatment and the URR is greater than 65%.

 Images During HD, patients commonly experience hypotension and cramps. Other more serious complications include infection and thrombosis of the vascular access.

 Images Peritoneal dialysis (PD) involves the instillation of dialysate into the peritoneal cavity via a permanent peritoneal catheter. The peritoneal membrane lines the highly vascularized abdominal viscera and acts as the semipermeable membrane. Solutes are removed from the blood across the peritoneum via diffusion and ultrafiltration. Excess plasma water is removed via ultrafiltration created by osmotic pressure generated by various dextrose or icodextrin concentrations.

 Images Patients on PD are required to instill and drain, manually or via automated systems, several liters of fresh dialysate each day. The more exchanges completed each day results in greater solute removal.

 Images Peritonitis is a common complication of PD. Initial empiric therapy for peritonitis should include intraperitoneal (IP) antibiotics that are effective against both gram-positive and gram-negative organisms.

 Images Nasal carriage of Staphylococcus aureus is associated with an increased risk of catheter-related infections and peritonitis. Prophylaxis with intranasal mupirocin (twice a day for 5 days every month) or mupirocin (daily) at the exit site can effectively reduce S. aureus infections.


The three primary treatment options for patients with end-stage renal disease (ESRD) are hemodialysis (HD), peritoneal dialysis (PD), and kidney transplantation. The United States Renal Data System (USRDS) is the national system that “collects, analyzes, and distributes” data relating to patients with ESRD or Stage 5 chronic kidney disease (CKD) in the United States.1 According to the 2011 USRDS, at the end of 2009, there are more than 550,000 patients in the United States with ESRD. Of these, 370,274 and 27,522 patients were being treated with HD and PD, respectively, and 172,553 had a functioning kidney transplant. In 2009, 116,395 new patients started therapy for ESRD (dialysis or transplantation) and more than 91,000 patients died. The vast majority of new dialysis patients are treated with HD. The number of patients treated with PD has steadily decreased since 2000.1 Although the number of patients who have received a kidney transplant has risen, transplantation has not kept pace with the growing prevalence of ESRD in the United States.1

Since 1972, the treatment of ESRD (both dialysis and kidney transplantation) has been paid for by Medicare. The total cost of ESRD in 2009 was 42.5 billion dollars, this includes Medicare costs (29 billion), Medicare patient obligation costs (4.2 billion), and non-Medicare costs (9.3 billion). Total Medicare spending for ESRD in 2009 rose by 3.1%. The Medicare spending does not include Part D expenditures, which were 1.55 billion in 2008. ESRD consumes a vastly disproportionate amount of resources; approximately 1% of the patients in the Medicare program have ESRD, yet 6% of the budget is consumed by the ESRD program. Although total spending for ESRD treatment continues to climb, per-patient spending (after adjusting for inflation) was fairly flat recently.1

There are some positive signs as it relates to public health and ESRD. Although the total number of dialysis patients is increasing in the United States, the number of new dialysis patients per total population has stabilized or slightly decreased from the highest value observed in 1997. The prevalence of ESRD continues to climb, reflective of reduced mortality and enhanced patient care. The primary diagnosis for new patients with ESRD is diabetes.1Chapter 29 provides a thorough discussion on the epidemiology of CKD.

This chapter serves as a primer on the principles and practice of dialysis and the complications associated with the delivery of dialysis treatments. The chapter focuses on HD and PD as the modalities most commonly employed for the management of ESRD (see Chap. 28 for a discussion of the role of renal replacement therapies in the management of acute kidney injury). The pertinent factors that should be considered before the initiation of dialysis are described. The morbidity and mortality associated with HD and PD are compared, as these considerations may influence the dialysis method chosen by patients and clinicians. Because dialysis by either method is not a generic procedure, the variants of HD and PD are detailed. The multiple types of vascular and peritoneal access used to provide HD and PD, including various catheters and surgical techniques, are illustrated. The concept of dialysis adequacy for each modality is briefly reviewed. Finally, the clinical presentation of the common complications of both dialytic therapies is presented, along with pertinent nonpharmacologic and pharmacologic therapeutic approaches. Patient-related videos that describe living with CKD, dialysis, and associated dialysis therapies are shown in Table 30-1. This information is included to provide the reader with a patient perspective into the disease and its associated therapies.

TABLE 30-1 Patient-Related Videos Relative to Dialysis Procedures and Therapies



Morbidity in patients receiving dialysis can be assessed in a number of different ways including tabulation of the number of hospitalizations per patient-year, the number of days hospitalized per patient per year, or the incidence of certain complications. The number of all-cause hospital admissions in dialysis patients per patient-year (1.9 hospitalizations per patient-year) have changed little since 1993. However, the rate of hospitalizations fell in 2006, to a rate approximately 4% less than that in 1993. Trends in hospitalization demonstrate an increase in hospitalization as a consequence of infection and cardiovascular disease and a decrease in hospitalizations as a consequence of vascular access problems. Patients with a functioning kidney transplant have a lower rate of hospitalization and shorter length of stay. Hospitalizations are more frequent for whites than for blacks, and the frequency and duration increase with age in both dialysis modality groups.1

The life expectancy of U.S. dialysis patients is markedly lower than that of healthy subjects of the same age and sex. In those older than 65 years, the risk of dying is twofold higher in dialysis patients compared with those with diabetes, cancer, heart failure, and cardiovascular disease.1 Approximately 50% of deaths in dialysis patients are cardiovascular related. In fact, those with CKD are more likely to die from cardiovascular disease before they reach ESRD. Infections, usually related to the dialysis access, are the second most common cause of death in dialysis patients. Although mortality is high in this patient population, improvement has been made and the overall patient mortality rate has fallen among dialysis patients since 1988. The changes in mortality rates are more impressive when the duration of a patient’s time receiving dialysis is considered. In patients receiving dialysis for fewer than 2 years, mortality rates decreased 25% since 1988. However, in those treated for 5 years or more, mortality rates increased 10%. These changes suggest that death is occurring later in the course of dialysis therapy. Regardless, in the United States, nearly two thirds of all dialysis patients die within 5 years of initiation of dialysis treatment, a life expectancy worse than patients with heart failure or numerous cancers.2

In addition to the morbidity and mortality discussed above a dialysis patient’s quality of life is generally poor. Quality-of-life assessments including the impact of dialysis treatment on these patients have been an area of considerable research.36 Additionally, in an effort to understand how these patients manage the constraints and difficulties of their life situations health care providers and researchers have provided commentaries and papers.711 For example, restrictions caused by thrice weekly HD and/or associated treatments have been shown to impact many areas of a patient’s life. These include but are not limited to, physical endurance, sex life, employment, social life, and dietary restrictions. Patients often complain of fatigue and fear of the unknown related to their disease and its progression. Although, the authors of this chapter may be able to describe the disruption to a patient’s life induced by this chronic disease only a kidney disease patient can adequately describe the three trips per week to the outpatient HD unit for a 3- to 4-hour HD session. The PD patient or the home HD patient may have some freedom from these restrictions, but this freedom comes with its own constraints (see the videos listed in Table 30-1).


The National Kidney Foundation’s Kidney Disease Outcome Quality Initiative (NKF-K/DOQI) recommends that planning for dialysis begin when patients reach CKD stage 4 (estimated glomerular filtration rate [eGFR] or creatinine clearance [CLcr] below 30 mL/min per 1.73 m2 [0.29 mL/s/m2]).12 Beginning the preparation process at this point allows adequate time for proper education of the patient and family and for the creation of a suitable vascular or peritoneal access. For patients choosing HD, a permanent arteriovenous (AV) access (preferably a fistula) should be surgically created when Clcr or eGFR falls below 25 mL/min (0.42 mL/s), serum creatinine is greater than 4 mg/dL (354 μmol/L), or 1 year prior to the anticipated need for dialysis.13

The primary criterion for initiation of dialysis is the patient’s clinical status: the presence of persistent anorexia, nausea, and vomiting, especially if accompanied by weight loss, fatigue, declining serum albumin concentrations, uncontrolled hypertension or congestive heart failure, and neurologic deficits or pruritus. Some nephrologists use critical lab values of serum creatinine or blood urea nitrogen as indicators of when to initiate dialysis. The 2006 update of the NKF-K/DOQI guidelines suggest that risks and benefits of dialysis should be evaluated when eGFR or CLcr is <15 mL/min per 1.73 m2 (<0.14 mL/s/m2).12,14 The advantages and disadvantages of HD and PD are depicted in Tables 30-2 and 30-3, respectively. These factors, along with the patients’ concomitant diseases, personal preferences, and support environments, are the principal determinants of the dialysis mode they will receive.2

TABLE 30-2 Advantages and Disadvantages of Hemodialysis


TABLE 30-3 Advantages and Disadvantages of Peritoneal Dialysis


Clinical Controversy…

There is debate over which dialysis treatment modality, HD or PD, is most desirable in terms of morbidity and mortality. Outcome studies have provided conflicting results. Although less than 10% of U.S. patients are treated with PD, nephrologists suggest many more ESRD patients could be treated with PD.

While the intent of this chapter is not to exhaustively compare and contrast HD and PD and the relative benefits of each, there is considerable debate in the literature regarding the mortality differences between HD and PD. A recent trial examining mortality in dialysis patients in the Netherlands found no difference between patients receiving either modality in the first 2 years. However after that mortality rates were higher in patients on PD.14 Most observational trials suggest that PD is associated with a survival advantage early in therapy, which wanes with increased treatment time. Well-designed studies are extremely difficult to conduct in this population and thus the question of superiority of one modality over the other is controversial. Differences in outcomes may be related to a wide array of confounding factors, such as the dose of dialysis, baseline patient health status, physician bias in modality selection, patient compliance with dialysis and medication therapy, or other unknown factors. For example, healthier patients tend to be directed toward PD and factors such as age, duration of dialysis, and comorbidities play an important role in the complex relationship between patient outcomes and mortality.15,16Without clear distinction between modalities in terms of many important outcomes, the selection of the optimal therapy for a given patient is challenging. The NKF-K/DOQI guidelines recommend that the timing of dialysis initiation is a compromise between maximizing patient QOL by extending the dialysis-free period while avoiding complications that will decrease the length and quality of dialysis-assisted life.12


Although HD was first successfully used in 1940, the procedure was not used widely until the Korean War in 1952. Permanent dialysis access was developed in the 1960s,17 which allowed routine use of HD in patients with ESRD. Subsequent decades brought advances in dialysis technology, including the introduction of more efficient and biocompatible dialyzer membranes and safer techniques. HD is now the most common type of renal replacement therapy for patients with ESRD.

Principles of Hemodialysis

Images HD, simply stated, consists of the perfusion of blood and a physiologic solution on opposite sides of a semipermeable membrane.18 Multiple substances, such as water, urea, creatinine, uremic toxins, and drugs, move from the blood into the dialysate, by either passive diffusion or convection as the result of ultrafiltration. Diffusion is the movement of substances down a concentration gradient; usually for endogenous waste products from the blood to dialysate; the rate of diffusion depends on the difference between the concentration of the solute in blood and dialysate, solute characteristics, that is size, water solubility, and charge, the dialyzer membrane composition, and blood and dialysate flow rates. Diffusive transport is rapid for small solutes, but slows with increasing molecular size. Other important diffusive solute transport factors include the membrane thickness, porosity, and the steric hindrance between the membrane pores and solute. Ultrafiltration is the movement of water across the dialyzer membrane as a consequence of hydrostatic or osmotic pressure and is the primary means for removal of excess fluid. Convection occurs when dissolved solutes are “dragged” across a membrane with fluid transport (if the pores in the dialyzer are large enough to allow them to pass). Convection can be maximized by increasing the hydrostatic pressure gradient across the dialysis membrane, or by changing to a dialyzer that is more permeable to water transport. These two processes of diffusion and convection can be controlled independently, and thus a patient’s HD prescription can be individualized to attain the desired degree of solute and fluid removal.18

Hemodialysis Access

Images Obtaining and maintaining access to the circulation has been a challenge for long-term use and success of HD.18 The AV fistula, AV graft, or venous catheter through which blood is obtained for dialysis is referred to as the dialysis access. Permanent access to the circulation may be accomplished by several techniques, including the creation of an AV fistula, an AV graft, or by the use of venous catheters (Fig. 30-1).19 The native AV fistula is created by the anastomosis of a vein and artery (i.e., the radial artery to the cephalic vein or the brachial artery to the cephalic vein). The native AV fistula has many advantages over other access methods. Fistulas have the longest survival of all blood-access devices and are associated with the lowest rate of complications such as infection and thrombosis. In addition, patients with fistulas have increased survival and lower hospitalization rates compared to other HD patients. Finally, the use of AV fistulas is the most cost-effective in terms of placement and long-term maintenance. Ideally, the most distal site (the wrist) is used to construct the fistula. This fistula is the easiest to create, and in the case of access failure, more proximal sites on the arm are preserved. Unfortunately, fistulas require 1 to 2 months or more to mature before they can be routinely utilized for dialysis. In addition, creation of an AV fistula may be difficult in elderly patients and in patients with peripheral vascular disease (which is particularly common in patients with diabetes).


FIGURE 30-1 The predominant types of vascular access for chronic dialysis patients are (A) the AV fistula and (B) the synthetic AV forearm graft. The first primary AV fistula is usually created by the surgical anastomosis of the cephalic vein with the radial artery. The flow of blood from the higher-pressure arterial system results in hypertrophy of the vein. The most common AV graft (depicted in green) is between the brachial artery and the basilic or cephalic vein. The flow of blood may be diminished in the radial and ulnar arteries since it preferentially flows into the low pressure graft.

Synthetic AV grafts, usually made of polytetrafluoroethylene, are another option for permanent AV access. In general, grafts require only 2 to 3 weeks to endothelialize before they can be routinely used. The primary disadvantages of this type of access when compared to an AV fistula are shorter survival of the graft, and higher rates of infection and thrombosis. The least-desirable HD access is via central venous catheters (CVCs), which, unfortunately, are commonly used in chronic HD patients. Venous catheters can be placed in the femoral, subclavian, or internal jugular vein. The main advantage of catheters is that they can be used immediately. Catheters are often used in small children, diabetic patients with severe vascular disease, the morbidly obese, and patients who have no viable sites for permanent AV access. Late referrals to a nephrology specialist and delayed placement of a more appropriate long-term access contribute to the overuse of venous catheters in chronic HD patients. The major problem with all venous catheters is that they have a short life span and are more prone to infection and thrombosis than either AV grafts or fistulas. Furthermore, some catheters are not able to provide adequate blood flow rates, which can limit the dose of dialysis delivered.1923 Regardless, tunneled dialysis catheters are used frequently for a variety of reasons including ease of insertion, pain-free dialysis, and immediate use. They are however associated with increased morbidity, mortality, and increased cost.24

The ESRD Clinical Performance Measures (CPM) Project examined quality of dialysis care markers, including anemia management, serum albumin, vascular access (for HD), and adequacy of dialysis. The report evaluated a sample population of adult in-center patients, 8,915 HD patients and 1,469 PD patients.25 At the end of 2005, 54% and 44% of incident and prevalent patients, respectively, were using AV fistulas for HD. The CPM Project’s goal is that 50% and 40% of incident and prevalent HD patients, respectively, should be using an AV fistula. Unfortunately, 21% of HD patients were using chronic catheters in 2005. This percent of patients using catheters is much higher than the CPM Project’s goal of <10%. The extensive use of catheters may be a result of the large population of patients who are not candidates for AV access, or that they are being used until permanent AV access can be accomplished. As noted earlier, timely referral to a nephrologist and vascular surgeon is necessary for the placement of the most appropriate access.

Hemodialysis Procedures

The HD system consists of an external vascular circuit through which the patient’s blood is transferred in sterile polyethylene tubing to the dialyzer via a mechanical pump (Fig. 30-2).26 The patient’s anticoagulated blood then passes through the dialyzer on one side of the semipermeable membrane and is returned to the patient. The dialysate solution, which consists of purified water and electrolytes, is pumped through the dialyzer countercurrent to the flow of blood on the opposite side of the semipermeable membrane. In most cases, systemic anticoagulation (with heparin) is used to prevent clotting of the HD circuit. The process of dialysis results in the removal of metabolic waste products and water and replenishment of body buffers.18 There are three broad categories of dialysis membranes: low flux, high efficiency, and high flux. Low-flux dialyzers, mostly made of cuprophane or cellulose acetate, have small pores that limit clearance to relatively small molecules (size ≤500 daltons) such as urea and creatinine. High-efficiency membranes have large surface areas and thus have a greater ability to remove water, urea, and other small molecules. High-flux membranes have larger pores that are capable of removing high-molecular-weight substances, such as β2-microglobulin, and vancomycin in addition to other larger molecular weight drugs.26,27 The primary reason to use high-efficiency and/or high-flux membranes is that clearance of both low- and high-molecular-weight substances is much greater than with the conventional membranes, allowing for shorter treatment times. To maximize the capacity or fully utilize the filter’s high flux membrane, high-efficiency and high-flux dialysis require blood flow rates greater than 400 mL/min, dialysate flow rates greater than 500 mL/min, and the use of strict controls on the rate of fluid removal. Typically these dialyzers are composed of polysulfone, polymethylmethacrylate, polyamide, cellulose triacetate, and polyacrylonitrile.26


FIGURE 30-2 In HD, the patient’s blood is pumped to the dialyzer at a rate of 300 to 600 mL/min. An anticoagulant (usually heparin) is administered to prevent clotting in the dialyzer. The dialysate is pumped at a rate of 500 to 1,000 mL/min through the dialyzer countercurrent to the flow of blood. The rate of fluid removal from the patient is controlled by adjusting the pressure in the dialysate compartment.

HD is usually prescribed three times weekly for 3 to 5 hours. The average duration of dialysis treatment session in the United States in 2005 was just over 3.5 hours.25 Larger patients generally require longer treatment times for adequate solute removal. This is a substantial time commitment for any patient undergoing HD and results in substantial loss of control over their life. Other types of HD have been explored in an effort to balance dialysis adequacy with patient outcomes and quality of life. Short daily HD, extended dialysis, and quotidian HD are all terms used to describe variants of HD in which dialysis is administered daily for shorter periods of time (2 to 2.5 hours) or as long, slow nocturnal treatments of up to 6 to 8 hours. The theoretical rationale for these treatments is to enhance the efficiency of HD and to reduce HD-induced hemodynamic instability. There is some evidence that these dialysis techniques result in improved clinical outcomes and that it may be a more cost-effective dialysis procedure.28,29 Both of these therapeutic options are usually delivered in the home. The delivery of traditional HD in the home setting is more commonly used in some countries such as New Zealand and Canada. Despite the perceived advantages, the use of home HD is uncommon in the United States, with less than 1% of dialysis patients receiving HD care at home.1 Prospective clinical trials are needed in this area to elucidate the role of these types of dialysis therapy.

Measures of Hemodialysis Adequacy

The optimal dose of HD for each individual patient varies and is that the amount of therapy above which there is no cost-effective increment in the patient’s quality-adjusted life expectancy. The two primary goals of the dialysis prescription are to achieve a desired dry weight and the adequate removal of endogenous waste products such as urea. Dry weight is the target postdialysis weight at which the patient is normotensive and free of edema. Measurement of urea removal, while imperfect, is the typical way in which dialysis adequacy is quantified. Referred to as the “delivered dose” of dialysis, urea removal is utilized as the surrogate for removal of other toxins.

The delivered or desired dose of dialysis in terms of solute removal can be expressed as the URR or the Kt/V (pronounced “K-T-over-V”). The URR is a simple concept and is easily calculated as:


The URR is frequently used to measure the delivered dialysis dose, however, it does not account for the contribution of convective removal of urea. The Kt/V is a unitless index based on the dialyzer clearance of urea (K) in L/h multiplied by the duration of dialysis (t) in hours, divided by the urea distribution volume of the patient (V) in liters.30 Kt/V is thus the fraction of the patient’s total body water that is cleared of urea during a dialysis session. Urea kinetic modeling, using computer software, is the optimal means to calculate the Kt/V.31 An in-depth discussion of the pros and cons of various methods of calculating and interpreting Kt/V is beyond the scope of this chapter. The reader is referred to other sources for more in-depth information.30,31

Images The NKF-K/DOQI recommends that the minimally adequate delivered dose of dialysis is a Kt/V of 1.2 (equivalent to an average URR of 65%).12 To achieve this goal, the recommended target prescribed Kt/V is 1.4 (equivalent to an average URR of 70%).12 Lower levels of dialysis treatment are thought to be associated with increased morbidity and mortality.18 Many nephrologists believe that even greater doses of dialysis would have positive outcomes in dialysis patients, and so the average dose of dialysis has been increasing in the United States. In 2004, the mean delivered Kt/V as reported by the CPM was 1.55.25 The Hemodialysis (HEMO) Study was designed to determine the effects of high-dose dialysis and the use of high-flux HD membranes on morbidity and mortality.32 The results of this prospective, randomized trial that assigned patients to either standard (Kt/V = 1.25) or high-dose (Kt/V = 1.65) dialysis with high-flux or low-flux membranes revealed that the risk of death was similar in both the standard and high-dose therapy and the low- and high-flux groups. Thus there does not appear to be any benefit in increasing the amount of dialysis above the current recommendations. Although many patients in the United States are well above the target Kt/V range, there is no reason to believe that nephrologists will begin to decrease their dose of dialysis. The HEMO study only enrolled patients who were on traditional thrice-weekly dialysis, thus the applicability of these findings to patients on more intensive regimens, such as daily or nocturnal HD regimens that provide long, frequent dialysis, remains to be determined,28,29,33 although early data indicate that these intensive HD regimens result in better blood pressure, anemia, and phosphate control.28 In those relatively few patients who are below the adequacy goal, the deficiency may be related to patient compliance with dialysis prescription (ending dialysis early) or low blood flow rates caused by access stenosis or thrombosis, or as a result of the use of catheters. Adequate dialysis may not be achieved in some patients despite compliance and sufficient blood flow. For these patients there are really only two options to increase urea clearance: use a larger membrane or increase the treatment time.


Patients with CKD defined as a glomerular filtration rate (GFR) <60 mL/min/1.73 m2 (<0.58 mL/s/m2) are more likely to have at least one additional comorbid disease such as diabetes, hypertension, cardiovascular disease (CVD), BMI ≥30 kg/m2. CKD patients are also more likely to be older (age ≥60). The most recent NHANES III data (2005 to 2010) report the prevalence of these comorbid diseases in CKD patients as diabetes 19.3%, hypertension 14.8%, CVD 24.3%, and BMI ≥30 kg/m2 11.7% with older age at 18.4%. When compared with the NHANES III 1988 to 1994 report the 2005 to 2010 report found that the largest increase in CKD patients was among those patients with CVD (25.4% to 40.8%) although the prevalence of CKD patients only increased from 12.3% to 14%.34

The pharmacotherapy management of CKD and any of these comorbid diseases requires multiple medications in addition to dietary restrictions and exercise. As CKD advances to ESRD the pill burden can substantially increase. The daily pill burden for ESRD patients is one of the highest for any chronic disease state. ESRD patients took a mean of 11 ± 4 medications (nine oral and two parenteral) which based on the oral medications resulted in a total pill burden of 19 pills (interquartile range 12) per day. This higher pill burden was associated with a lower quality of life and was not associated with better control of serum phosphorus, a major disease-related problem in ESRD patients.35

Patients receiving renal replacement therapy need to be compliant with not only diet and drugs but also dialysis whether this treatment is daily or three times a week. Compliance is essential to manage these diseases but can seem overwhelming for the patient. Therefore, a good working relationship with healthcare providers including their pharmacist can provide the information and support patients require to actively managing these diseases.


Images Complications associated with HD therapy are significant and can limit therapy efficacy. These complications that occur during the actual therapy (intradialytic), as well as those associated with vascular access are discussed in this chapter.3638

Intradialytic Complications

The most common complications that occur during the HD procedure include hypotension, cramps, nausea and vomiting, headache, chest pain, back pain, and fever or chills.37,38 Table 30-4 lists these complications and their etiology and predisposing factors.

TABLE 30-4 Common Complications During Hemodialysis38


A decrease in blood pressure is often noted during HD, but a symptomatic decline in blood pressure that requires nursing or medical intervention can lead to a decrease in the effectiveness of this treatment.37Intradialytic hypotension (IDH) is primarily related to the rate and amount of fluid removed during32 typical treatments, although other causes, as listed in Table 30-4, may also play a role.39 Other symptoms such as nausea and cramping are often present during acute hypotensive episodes. The replacement of acetate with bicarbonate as the dialysate buffer, the use of volumetric ultrafiltration controllers, as well as individualized dialysate sodium concentrations and modeling have helped reduce the incidence of hypotension.4042

Skeletal muscle cramps complicate 5% to 20% of HD treatments. Although the pathogenesis of cramps is multifactorial, plasma volume contraction and decreased muscle perfusion caused by excessive ultrafiltration are frequently the initiating events.37,38 Another complication pruritus, which may appear to increase in severity during the HD treatment, is actually a complication of CKD and the management of this condition is discussed in Chapter 29.

Vascular Access Complications

The maintenance of vascular access patency is critical for HD patients since this access is essential for treatment. Aneurysm and stenosis have been reported with AV fistulas and grafts and resolution of this is primarily by surgical means. Thrombosis and infection are the most common vascular access complications with the highest occurrence found in patients with a cuff catheter compared with those with an AV graft or AV fistula.38,43,44

Vascular access dysfunction is usually identified by a decrease in blood flow through the access (blood flow <300 mL/min) over a period of days to weeks. Ultrasound, venography, or computed tomography scans can be used for a definitive diagnosis.22,45,46 Catheter thrombosis can form either inside (intrinsic) or outside (extrinsic) the catheter. The occlusion can form within the lumen at the tip or develop a fibrin sleeve around the catheter where this fibrin sleeve can serve as a nidus for infection and ultimately require catheter removal.47,48

Infection is the second leading cause of mortality in HD patients.49 The risk of sepsis-related death is 100 times greater in dialysis patients than the general population and those with an indwelling catheter have the highest risk.50Common skin flora such as S. aureus and coagulase-negative staphylococcus are frequently the source of infection, but gram-negative bacterial and fungal causes must not be overlooked. Catheter-related infections develop at the insertion site, hub, or both. The infection source for long-term catheters such as a tunneled catheter is usually the hub where bacteria can enter the blood leading to a bloodstream infection.51,52 Overall HD access with a catheter is associated with higher rates of bacteremia, osteomyelitis, septic arthritis, endocarditis, and death as well as increased treatment costs compared with an AV fistula or AV graft.43



Acute management of IDH includes placing the patient in the Trendelenburg position, decreasing the ultrafiltration rate, lowering the dialysate temperature, modifying dialysate electrolyte concentrations, and/or administering normal or hypertonic saline.3641 IDH may not occur during each HD session and patient intravariability could necessitate further HD customization. Hypertensive medications administered the day prior to HD therapy may contribute to IDH; therefore, a careful review of all medications including antihypertensive therapies is warranted. Patients with IDH should be counseled to take their blood pressure medications after HD.

IDH is generally related to an insufficient cardiac response to reduced circulating blood volume; therefore, most treatments are directed toward restoring or maintaining adequate blood vessel perfusion in these patients. For example decreasing the dialysate temperature to 36.5°C (97.7°F) may help reduce core body temperature, which can decrease vasodilation.53,54 If nonpharmacologic interventions are not adequate to prevent or reduce the incidence of symptomatic IDH then pharmacologic interventions should be considered (Table 30-5). Several pharmacologic options are discussed in this section.

TABLE 30-5 Management of Hypotension


Midodrine, an α1-adrenergic agonist prodrug (active metabolite desglymidodrine), with peripheral vasoconstrictive properties has been effective with managing IDH. Midodrine administered prior to HD in doses ranging from 2.5 to 10 mg resulted in postdialysis blood pressure elevations and improvement of symptoms. An average increase of systolic and diastolic blood pressures was 12.4 and 7.3 mm Hg above the values in control patients, respectively.55An 8-month long study found that midodrine 10 mg given 30 minutes prior to dialysis resulted in correction of hypotension without any adverse events.56 Oral midodrine (5 mg) given twice daily can increase blood pressure in HD patients with chronic hypotension on nondialysis days.57 It is important to note that the effects of midodrine are probably best in patients with hypotension related to autonomic dysfunction as opposed to other causes of hypotension. The main adverse effect related to midodrine is urinary retention, but patients with peripheral vascular disease should be monitored for digital or lower limb ischemia.58

Other potential therapeutic agents for IDH include levocarnitine, sertraline, and intranasal desmopressin acetate (DDAVP). The IV administration of levocarnitine (20 mg/kg at the end of each dialysis session) reduced hypotensive episodes from 17 to 7 (P <0.02) in a study of 38 patients.59,60 The high cost and limited data on levocarnitine, however, preclude a strong recommendation for its use. Sertraline has demonstrated efficacy in some,61,62 but not all studies.63 A study of 17 IDH patients compared DDAVP to placebo (saline nasal spray).64 Overall, the use of DDAVP increased post-HD blood pressure and decreased the incidence of IDH. In addition, fludrocortisone has been suggested as a potential agent for symptomatic hypotension.65 These medications have limited clinical evidence and should be used with caution in patients with IDH.

Muscle Cramps

Nonpharmacologic interventions related to dialytic therapy may help alleviate muscle cramps. These measures include adjusting the ultrafiltration rate to avoiding hypotension, volume contraction, or hypoosmolality. Other methods to reduce muscle cramps are compression devices, moist heat, massage, exercise, stretching or muscle flexing and should be considered first to minimize adverse consequences (Table 30-6).37,66

TABLE 30-6 Management of Cramps


Both vitamin E and quinine significantly reduce the incidence of muscle cramps.6769 Quinine is usually well tolerated, but rarely may cause temporary sight and hearing disturbances, thrombocytopenia, or GI distress. Furthermore, quinine tends to increase plasma digoxin concentrations and may enhance the effect of warfarin. This constellation of adverse events prompted the withdrawal of quinine from the over-the-counter market in 1995 and prescription quinine can no longer be marketed for leg cramps.

A randomized, double-blind, placebo-controlled trial demonstrated that both vitamin E (400 mg) and vitamin C (250 mg) reduce the frequency of cramps in dialysis patients.70 The combination of these two drugs had an additive effect. Although these data further strengthen the case for vitamin E, it is unclear what role oral vitamin C would play since many patients are on a renal multiple vitamin containing vitamin C (the current study restricted all vitamin products for 1 month prior to the study). Furthermore, there is some concern that oxalate, a metabolite of vitamin C, may accumulate in dialysis patients and result in systemic oxalosis.

Exogenous administration of creatine might have some beneficial effects on muscle cramps in dialysis patients.71 Ten patients with intradialytic muscle cramps were randomized to either creatine (12 mg before dialysis) or placebo. The frequency of muscle cramps decreased 60% in the creatine group, while there were no differences in the placebo group. Although serum creatinine concentrations rose in the treatment group, no side effects were noted.71 Certainly more research in this area is needed before creatine supplementation can be recommended for the prevention and treatment of muscle cramps during HD.

The relationship of elevated calcium, phosphorus, and intact parathyroid hormone in relation to muscle pain, cramps, pruritus, and dry skin (xerosis) were evaluated in 1,469 HD and PD patients.72 At baseline approximately 67% of patients suffered from at least one of these symptoms. After 4 years of follow-up, those patients with diminished or no symptoms had lower serum phosphorus concentrations.72 This study suggests that adequate dialysis along with dietary controls can help reduce muscle pain, cramps, itching, and dry skin in dialysis patients.

Shakuyaku-kanzo-to, a combination of peony and licorice root from traditional Japanese and Chinese medicine, was studied in 23 HD patients for acute treatment of muscle cramps. The ultrafiltration rate was reduced to zero and shakuyaku-kanzo-to (2.5 gram granule) was administered when a patient complained of cramping during HD. These interventions resulted in a muscle cramp resolution rate of 88.5% that occurred between 5 and 10 minutes.73 It is difficult to determine if muscle cramp cessation was due to stopping HD fluid removal, shakuyaku-kanzo-to, or the combination of both treatments. Previous studies have examined the use45 of shakuyaku-kanzo-to for the frequency and severity of muscle cramps but the results were inconsistent and a few patients had an increase in symptoms.74

Pharmacologic interventions to diminish muscle cramps are limited and currently vitamin E has the strongest evidence-based clinical trials and its safety profile. Quinine sulfate is available as Qualaquin 324 mg capsule (URL Pharma, Philadelphia, PA) but is FDA approved only for malaria. The FDA has warned against the off-label use of quinine for muscle cramps because of potential serious side effects related to its use. The dosage for HD-related muscle cramps is one capsule (324 mg) either at bedtime or 1 to 2 hours prior to HD.

Vascular Access Thrombosis

Prevention of vascular access thrombus formation is a key component to maintain this lifeline for HD patients. Multiple oral and IV anticoagulant and antiplatelet agents and IV thrombolytic agents have been studied for vascular access patency. Several of these therapeutic options are discussed in this section.

Clinical Controversy…

The use of oral anticoagulant or antiplatelet agents to maintain vascular access patency is controversial since the risk may be greater than the benefit. Studies have reported conflicting results and serious adverse reactions in HD patients that may increase morbidity and mortality.

The use of oral antiplatelet agents to prevent vascular access thrombosis has been controversial since efficacy is not well-established and there is an increased risk of bleeding.45,46,75 Extended-release dipyridamole with aspirin was studied in 649 patients with a newly placed arteriovenous graft (AVG). Patients received either treatment or placebo and were followed for 1 month after the loss of graft patency. At 1 year, unassisted patency was 28% in the treatment group compared to 23% in the placebo group. Adverse events were slightly higher in the treatment group (55% vs. 53%), but bleeding rates were similar between groups (12%).76 Daily aspirin use has also been evaluated in the maintenance of AV fistula in HD patients.77 This observational cohort study reported that consistent aspirin use was associated with a lower rate of AV fistula failure and no increase in new GI bleeding compared to patients not receiving aspirin. Consistent aspirin use was studied in this trial, but not aspirin dose. The use of warfarin to maintain vascular access patency for dialysis patients has become controversial with some trials suggesting an increase in morbidity and mortality with the use of warfarin.7881 Warfarin dosing regimens and adjusted international normalized ratio (INR) targets have also been examined in HD patients.80 Much of the recent literature has suggested that warfarin should be used with caution in HD patients. These patients generally require a lower dose and are at a much higher risk of a major hemorrhagic event.78,79,81

The effect of fish oil supplementation for AVG patency was reported in HD patients (n = 201).82 Patients were randomized to receive either a combination of eicosapentaenoic acid (EPA) 400 mg and docosahexaenoic acid (DHA) 200 mg or placebo for 12 months after AVG placement. The loss of native AVG patency was lower in the fish oil (48%) versus placebo (62%) groups, but the proportion of graft malfunction was not significantly different (P= 0.06). Fish oil may have some benefit for patients with an AVG since time to thrombus was longer and thrombus rates were about half that of placebo.82

Patients whose HD access is a venous catheter may benefit from a solution instilled in the catheter lumen between HD sessions. This is referred to as a catheter locking solution and has been used to maintain catheter patency.45,83Many HD centers use unfractionated heparin (UFH) as a catheter locking solution, but alternatives to UFH are being reported. The Citrate 4% versus heparin and the reduction of thrombosis study (CHARTS) was a prospective, randomized study examining sodium citrate 4% (n = 32) versus UFH (n = 29) and the reduction of catheter thrombosis in HD patients.84 Catheter dysfunction occurred more often in the UFH (44.8%) versus the citrate (40.6%) groups (P = 0.799). Systemic bleeding events were significantly greater with UFH (n = 21) compared with citrate (n = 7; P = 0.035). Overall a catheter locking solution of sodium citrate 4% was as effective as UFH but may offer a better safety profile at a reduced cost.84

CVC patency was compared in HD patients (n = 225) randomized to receive either a catheter lock solution of regimen that alternated UFH and recombinant tissue plasminogen activator (rt-PA) or UFH alone.85 Patients in the rt-PA group had rt-PA 1 mg instilled per catheter lumen (2 mg total) once a week and UFH 5,000 units/mL per lumen on the remaining treatment days. The heparin-only group received the same heparin lock solution dose after each HD session. Catheter malfunction occurred more often in the heparin-only (43.8%) versus rt-PA (20%) group (P = 0.02). A catheter lock solution regimen including rt-PA is considerably more expensive than an UFH-only regimen. The study investigators concluded that the increased drug cost is offset by decreasing catheter malfunction rates and possibly avoiding hospitalization for these patients.85

The therapeutic alternatives for venous catheter thrombosis are listed in Table 30-7. If a catheter-related thrombus is suspected, a forced saline flush should be used to clear the catheter, followed by installation of a thrombolytic. A number of studies have been published using alteplase8688 and reteplase89,90 for thrombosed HD catheters. The initial reperfusion rates for both alteplase and reteplase were approximately 90%. A systematic review of thrombolytics in HD catheters to restore function compared the efficacy, safety, and cost of alteplase, reteplase, and teneteplase.91 The authors found the most evidence with alteplase, which is the only agent of the three agents, FDA approved, for venous catheter clearance. The venous catheter clearance rates were reteplase (88 ± 4%), alteplase (81 ± 37%), and tenecteplase (41 ± 5%). The cost analysis favored the use of reteplase: however to attain these savings reteplase must be batch prepared. It also can be stored frozen to extend its shelf-life.91

TABLE 30-7 Management of Hemodialysis Catheter Thrombosis


Alteplase is available commercially as a 2 mg/2 mL vial and can be administered as a short dwell for 30 to 60 minutes, as a long dwell or left in the catheter between treatments. A study evaluating patency rates between alteplase short-term (1 hour) and long-term (52 hours) dwells found no difference in patency rates between the short or long dwells.92 Alteplase has also been given as a short infusion. Infusion doses reported in the literature include 2 mg per hour over 4 hours93,94 for blocked catheter and 1 mg per hour over 4 hours for a sluggish blood flow.93 Infusions may theoretically be more efficacious than the dwell technique because the thrombus is only exposed to the thrombolytic at the very tip of the catheter. Another consideration is dwell versus push techniques for thrombolytic therapy. A prospective, randomized study compared the efficacy of an alteplase dwell protocol (30 to 120 minutes) to a push protocol (30 minutes) for restoring occluded HD catheter function (n = 82).95 Adequate blood flow was restored more often in the push protocol (32/39 catheters) compared with the dwell protocol (28/43 catheters). This study showed that a push protocol with alteplase was as effective and safe for managing HD catheter dysfunction and might be more practical than a dwell technique.95


HD patients who develop a fever during treatment should immediately be evaluated for infection; blood cultures should be collected prior to the administration of any prophylactic antibiotics. In cases when an AV fistula infection is suspected empiric broad-spectrum antibiotic therapy must be initiated usually with vancomycin plus an aminoglycoside. Antibiotic treatment should continue for a total of 6 weeks and therapy should be tailored to culture sensitivities. Unfortunately, a suspected infection in an AVG may require more than antibiotic therapy alone and a surgical procedure to remove the infected graft material may be needed. A suspected infection in a temporary catheter may warrant catheter removal and if possible obtain a culture of the catheter tip.9698 Since catheter-related infections are more common than infections with an AV fistula or AVG, preventative care approaches very important for HD patients. Treatment with systemic antibiotic plus an antimicrobial catheter lock solution may be needed. Preventative care includes minimizing the use and duration of catheters, proper disinfection and sterile technique, and the use of an antimicrobial ointment at the exit site (mupirocin 2%, povidone-iodine). Dialysis unit protocols that employ universal precautions, such as limit manipulation of the catheter, skin preparation with an antiseptic wash (tincture of iodine, chlorhexidine, etc.), and the use of face masks by the patient and caregiver, can significantly reduce the incidence of catheter-related bacteremia.96,97,99 Topical application of 2% mupirocin ointment to a tunneled HD catheter exit site after each HD session was shown in one study to increase infection-free days from 55 (control group) to 108 (treatment group).100 However, there are concerns that the use of mupirocin prophylaxis may lead to the development of resistant S. aureus. A 6-year study that prospectively monitored HD patient CVC infection rates used a once-a-week application of a topical polysporin triple ointment (bacitracin/gramicidin/polymyxin B) to CVC exit sites as part of standard CVC care did not report an increase in S. aureus resistance.101 An alternative to mupirocin may be the use of topical medical grade Leptospermum honey (Medihoney™ Pty Ltd Derma Sciences, Inc., Princeton, NJ) to catheter exit sites. In a preliminary study medical-grade Leptospermum honey was found to be as effective as mupirocin in reducing catheter infections.102

The Infectious Disease Society of America (IDSA) has published comprehensive guidelines (2009 and 2011) regarding catheter care and the diagnosis and management of catheter-related infections.97,99 The 2006 Kidney Dialysis Outcomes Quality Initiative (KDOQI) guidelines also provide an outline for patient care.45 However, there are differences in what IDSA has proposed and what is practical in the outpatient chronic HD setting for HD patients with an indwelling catheter. In an effort to protect potential HD access sites peripheral blood draws are often avoided in HD patients. Blood cultures are generally obtained from the blood tubing connecting the catheter to the HD machine. A full-course of antimicrobial treatment is warranted if these blood cultures are found to be positive.97,99 Empiric therapy with coverage for both gram-positive and gram-negative bacteria should be initiated after the blood cultures are obtained. The incidence of methicillin-resistant Staphylococcus aureus (MRSA) bacteremia is high enough to warrant initial treatment with vancomycin for gram-positive coverage and either an aminoglycoside or third-generation cephalosporin for gram-negative coverage.97,99 Therapy should be adjusted once blood cultures identify an organism. For example if the isolated organism is methicillin-sensitive S. aureus, therapy may be changed to IV cefazolin (20 mg/kg, rounded to the nearest 500 mg) after each dialysis session.103,104 Antibiotic selection should be based on bacterial coverage and optimizing the pharmacokinetics of administering a dose after a HD treatment session without requiring additional dosages between HD sessions. Examples of antimicrobial agents that meet these objectives are vancomycin, cefazolin, ceftazidime, daptomycin, and aminoglycosides.97,103106

The IDSA guidelines recommend that the infected catheter should be removed if S. aureusPseudomonas species, or Candida species are identified as the infectious cause. Although removal of the catheter is warranted since up to 75% of patients have a recurrence of bacteremia after completing a course of antibiotics, this is not always possible in HD patients. Options such as replacing the catheter over a guidewire or using a catheter lock solution in conjunction with IV antibiotics have been used as an alternative.97,99 Recent studies have suggested that between 62% and 70% of catheters can be salvaged using this technique (as defined by absence of fever without loss of catheter).97,99 The IDSA guidelines recommend the use of catheter lock solutions as adjunctive therapy after each dialysis session for 10 to 14 days in patients that their catheter was not removed and bacteremia symptoms resolved in 2 to 3 days. The IDSA recommendations for antibiotic therapy are listed in Table 30-8.

TABLE 30-8 Management of Hemodialysis Access Infection


As opposed to treatment, catheter locking has also been studied to prevent infection and thrombosis in HD catheters.107 A meta-analysis of randomized control trials of catheter-related bacteremia and antimicrobial lock solutions identified eight studies with 829 patients and more than 90,100 catheter days. Overall analysis found the use of an antimicrobial lock solution reduced the risk of a catheter-related infection (relative risk [RR] 0.32; 95% confidence interval [CI] 0.10 to 0.42).108 A recent study not included in this meta-analysis compared lock solutions of UFH 1,000 units/mL to a combination of gentamicin 320 mcg/mL with 4% sodium citrate. The rate of blood stream infections was significantly lower (P = 0.003) and time to first bacteremia was significantly longer (P = 0.005) with combination solution of gentamicin and citrate compared with UFH.109

The data examining the use of catheter lock solutions for treatment and prevention of catheter-related infections are growing, but there is still a concern regarding antibiotic resistance with the wide use of antibiotics in catheter locks. Currently, NKF-K/DOQI does not recommend routine locking of catheters with antibiotics.


Although the concept of peritoneal lavage has been described as far back as the 1700s, it wasn’t until the 1920s that PD was first employed as an acute treatment for uremia. It was used infrequently during subsequent years until the concept of PD as a chronic therapy for ESRD was proposed in the 1960s. By the mid-1970s, PD was used relatively commonly and over the ensuing years the number of patients receiving PD increased slowly until the early 1980s. At that time, several innovations in PD delivery systems were introduced, such as improved catheters and dialysate bags. These innovations led to improved outcomes, decreased morbidity, and a corresponding increase in the use of PD as a viable alternative to HD for the treatment of ESRD. However, even with these proposed advantages, there has been a declining use of PD in the world over the past decade.2 Some patients—such as those with more hemodynamic instability (e.g., hypotension) or significant residual kidney function, and perhaps patients who desire to maintain a significant degree of self-care may be better suited to PD rather than to HD. There is some debate over important outcomes for patients on PD. Table 30-3 describes some advantages and disadvantages of PD.

Principles of Peritoneal Dialysis

Images The three basic components of HD—namely, a blood-filled compartment separated from a dialysate-filled compartment by a semipermeable membrane—are also present in PD.110 In PD, the dialysate-filled compartment is the peritoneal cavity, into which dialysate is instilled via a peritoneal catheter that traverses the abdominal wall. The contiguous peritoneal membrane surrounds the peritoneal cavity. The cavity, which normally contains about 100 mL of lipid-rich lubricating fluid, can expand to a capacity of several liters. The peritoneal membrane that lines the cavity functions as the semipermeable membrane, across which diffusion and ultrafiltration occur. The membrane is classically described as a monocellular layer of peritoneal mesothelial cells. However, the dialyzing membrane is also comprised of the basement membrane and underlying connective and interstitial tissue. The peritoneal membrane has a total area that approximates body surface area (approximately 1 to 2 m2). Blood vessels supplying and draining the abdominal viscera, musculature, and mesentery constitute the blood-filled compartment.

Unlike HD, the crucial components of PD cannot be manipulated to maximize solute and fluid removal. Because the blood is not in intimate contact with the dialysis membrane as it is in HD, metabolic waste products must travel a considerable distance to the dialysate-filled compartment. In addition, unlike HD, there is no easy method to regulate blood flow to the surface of the peritoneal membrane, nor is there a countercurrent flow of blood and dialysate to increase diffusion and ultrafiltration via changes in hydrostatic pressure. Similarly there is no easy means available to manipulate the peritoneal membrane. Most of the control in dialysis dosing during PD involves alterations in dialysate volume, dwell time, and the number of exchanges per day. For these reasons, PD is a much-less-efficient process per unit time as compared with HD, and must, therefore, be a virtually continuous procedure to achieve acceptable goals for clearance of metabolic waste products.

Peritoneal Dialysis Access

Access to the peritoneal cavity is via the placement of an indwelling catheter. Many types are available and Figure 30-3 shows an example.110 Most catheters are manufactured from silastic, which is soft, flexible, and biocompatible. A typical adult catheter is 40 to 45 cm long, 20 to 22 cm of which are inside the peritoneal cavity. Placement of the catheter is such that the distal end lies low in a pelvic gutter. The center section of the catheter has one or two cuffs made of a porous material. This section is tunneled inside the anterior abdominal wall so that the cuffs provide mechanical support and stability to the catheter, a mechanical barrier to skin organisms, and prevent their migration along the catheter into the peritoneal cavity. The cuffs are placed at different sites surrounding the abdominal rectus muscle. The remainder of the central section of the catheter is tunneled subcutaneously before exiting the abdominal surface, usually a few centimeters below and to one side of the umbilicus.


FIGURE 30-3 Diagram of the PD catheter placement through the abdominal wall into the peritoneal cavity.

The placement of the catheter exit site is one of the factors related to the development or prevention of exit-site infections and peritonitis. The external section of most peritoneal catheters ends with a Luer-Lok connector, which can be connected to a variety of administration sets. These catheters can be used immediately if necessary, provided that small initial volumes are instilled; however, a maturation period of 2 to 6 weeks is preferred.

Peritoneal Dialysis Procedures

Images In the United States, several variants of PD are clinically utilized. All variants of PD require the placement of a dialysis solution to dwell in the peritoneal cavity for some period, removing the spent dialysate, and then repeating the process. The prescribed dose of PD may be altered by changing the number of exchanges per day, by altering the volume of each exchange, or by altering the strength of dextrose in the dialysate for some or all exchanges. Increasing any one of these variables increases the effective osmotic gradient across the peritoneum, leading to increased ultrafiltration and diffusion (solute removal). If the dwell time is extended, equilibrium may be reached, after which time there will be no further water or solute removal. In fact, after a critical period, reverse water movement may occur.110,111

In a basic continuous ambulatory peritoneal dialysis (CAPD) system, the patient or caregiver is manually responsible for performing the prescribed number of dialysate exchanges. The patient is connected to a bag of prewarmed peritoneal dialysate via the PD catheter, by a length of tubing called a transfer set. The most common transfer set used is the Y transfer set. This consists of a Y-shaped piece of tubing that is attached at its stem to the patient’s catheter, leaving the remaining two limbs of the Y attached to dialysate bags, one filled with fresh dialysate and the other empty. The spent dialysate from the previous dwell is drained into the empty bag, and the peritoneum is subsequently refilled from the bag containing fresh dialysate. The Y set is then disconnected and the bag containing the spent fluid and the empty bag that had contained fresh dialysate are detached and discarded. Typically a patient instills 2 to 3 L of dialysate three times during the day with each exchange lasting 4 to 6 hours, and then a single dialysate exchange overnight lasting 8 to 12 hours. At the end of the prescribed dwell period, a new Y set is attached and the process is repeated. The process of outflow, aseptic manipulation of the administration set and catheter, and inflow requires a total time of approximately 30 minutes.111

CAPD involves performing the dialysate exchanges manually, whereas automated systems, collectively termed automated peritoneal dialysis (APD), perform the exchanges with a device referred to as a cycler. APD systems are designed for patients who are unable or unwilling to perform the necessary aseptic manipulations, and for those who require more dialysis. APD provides an automated cycler that performs the exchanges. The device is set up in the evening, and the patient attaches the peritoneal catheter to it at bedtime. The machine performs several short-dwell exchanges (usually 1 to 2 hours) during the night. This permits a long cycle-free daytime dwell of up to 12 to 14 hours. Typical APD regimens involve total 24-hour exchanges of approximately 12 L, which include one or more daytime dwells.112This type of regimen is sometimes referred to as APD with a “wet” day. The APD variant, nightly intermittent PD, has a similar theme, except that the peritoneal cavity tends to be dialysate free during the day. This type of regimen is frequently referred to as APD with a “dry” day. A number of variants exist and depend largely on equipment availability, patient and prescriber preference, and whether the patient retains any residual renal function (RRF), which influences the quantity of dialysis prescribed.111

The APD systems include continuous cycling PD, tidal PD, and nightly intermittent PD.111 The prototypic form of APD is usually a hybrid between CAPD and continuous cycling PD, in which some of the daily exchanges (usually the overnight exchanges) are completed using an automated device. Recent advances in PD procedures involve using continuous flow peritoneal dialysate.113,114 This technique maintains a fixed IP volume and rapid, continuous movement of dialysate into and out of the peritoneal cavity. To accomplish this, two PD catheters (an inlet and outlet catheter) and a means of generating a large volume of sterile dialysate are required. Dialysate is generated via conventional HD equipment or sorbent technology. In continuous flow peritoneal dialysate, clearance of small solutes is three to eight times greater than with APD, and approximates that with daily HD.113 Potential applications of continuous flow peritoneal dialysate include daily home dialysis, treatment of acute renal failure in the intensive care unit, and ultrafiltration of ascites.113

Peritoneal Dialysis Solutions

All forms of PD use dialysate solutions, which are commercially available in volumes of 1 to 3 L in flexible polyvinyl chloride plastic bags. It is beyond the scope of this chapter to exhaustively review all the options, but the most commonly used solutions which are commercially available contain glucose or icodextrin with varying concentrations of electrolytes, such as sodium (132 mEq/L [132 mmol/L]), chloride (96 mEq/L [96 mmol/L]), calcium (2.5 to 3.5 mEq/L [1.25 to 1.75 mmol/L]), magnesium (0.5 mEq/L [0.25 mmol/L]), and lactate (40 mEq/L [40 mmol/L]). Dialysate pH is maintained at 5.2.66,110These solutions may contain dextrose (1.5%, 2.5%, 3.86%, or 4.25%) or icodextrin (a glucose polymer) at a concentration of 7.5%. The dextrose solutions are hyperosmolar (osmolarity ranges from 345 to 484 mOsm/L) and induce ultrafiltration (removal of free water) by crystalline osmosis. Dextrose is not the ideal osmotic agent for peritoneal dialysate because these solutions are not biocompatible with peritoneal mesothelial cells or with peritoneal leukocytes.83 The cytotoxic effects on these cells are mediated by the osmolar load and the low pH of the solutions, as well as the presence of glucose degradation products formed during heat sterilization of these products. Icodextrin PD solution contains icodextrin, a starch-derived glucose polymer. It has an osmolality of 282 to 286 mOsm/kg (282 to 286 mmol/kg), which is isoosmolar with serum. Icodextrin produces prolonged ultrafiltration by a mechanism resembling colloid osmosis resulting in ultrafiltration volumes similar to those with 4.25% dextrose. Icodextrin may have fewer of the metabolic effects associated with dextrose, such as hyperglycemia and weight gain. It is indicated for use during the long (8 to 16 hours) dwell of a single daily exchange in CAPD and APD patients.115 Outside of North America, lower glucose degradation product dialysate solutions are also available with similar solute concentrations, but with a pH of 7.3.110 These newer, biocompatible dialysate solutions are claimed to be less harmful to the peritoneal membrane and preserve RRF to a greater extent than currently available standard solutions.116,117 Preservation of RRF in PD and HD patients is important as it has been shown to decrease mortality.118 Moreover, preservation of RRF in PD patients has been shown to increase the time to the first episode of peritonitis.119 However, the putative benefits of the biocompatible dialysate solutions have not been completely borne out. In a study that compared biocompatible to standard dialysate solutions, researchers found that the biocompatible solutions did not slow the rate of decline in GFR as compared to standard solutions, but they did delay the onset of anuria and reduced the incidence of peritonitis better.120

Measures of Peritoneal Dialysis Adequacy

The adequacy of PD is determined by clinical assessment, solute clearance determination, and fluid removal. As in HD, the clearance of urea, a product of protein catabolism, can be quantified by calculating Kt/V. The calculations determine a daily Kt/V, which is converted to a weekly value that is relevant for PD patients.121

PD adequacy is a major issue, which has received considerable attention during the last 10 years. The most recent NKF-K/DOQI guidelines recommend that patients on PD have at least a total Kt/V of 1.7 per week.122,123 It is important to note that RRF may provide a significant component of the total Kt/V. Patients may commence PD with a residual CLcr of approximately 9 to 12 mL/min, which contributes a renal Kt/V of 0.2 to 0.4. Over a period of 1 to 2 years, RRF tends to progressively deteriorate. Because total Kt/V is the sum of PD Kt/V and renal Kt/V, the total Kt/V will progressively diminish unless PD Kt/Vis increased (by increasing the prescribed dose of PD) to compensate for the reduced renal Kt/V.

For patients producing <100 mL urine per day, the weekly Kt/V dose of 1.7 must be provided entirely by peritoneal clearance. For patients producing >100 mL urine per day, combined renal and peritoneal urea clearances must exceed the weekly Kt/V dose of 1.7.122,123 The weekly Kt/V dose should be measured within the first month of PD initiation and at least once every 4 months thereafter. It is imperative to detect subtle decreases in RRF along with noncompliance to make necessary alterations to the prescribed PD dose to attain adequate clearance of waste products.

The NKF-K/DOQI guidelines also stress the importance of preserving RRF in PD patients because it is associated with decreased mortality in PD patients. Typical measures to maintain RRF include preferential use of angiotensin-converting enzyme inhibitors or receptor blockers in all patients, regardless of blood pressure, and avoidance of medications or procedures that are associated with insults to the kidney (e.g., nonsteroidal anti-inflammatory drugs, -cyclooxygenase-2 inhibitors, aminoglycosides, radiocontrast dyes, withdrawal of immunosuppressant therapies from a transplanted kidney, hypovolemia, urinary tract obstruction, and hypercalcemia).122

Complications of Peritoneal Dialysis

Mechanical, medical, and infectious problems complicate PD therapy. Mechanical complications include kinking of the catheter and inflow and outflow obstruction; excessive catheter motion at the exit site, leading to induration and possible infection and aggravation of tissues; pain from impingement of the catheter tip on the viscera; or inflow pain resulting from a jet effect of too rapid dialysate inflow.

Table 30-9 lists the numerous medical complications of PD. An average PD patient absorbs up to 60% of the dextrose in each exchange. This continuous supply of calories leads to increased adipose tissue deposition, decreased appetite, malnutrition, and altered requirements for insulin in diabetic patients. Fibrin formation in dialysate is common and can lead to obstruction of catheter outflow. Infectious complications of PD are a major cause of morbidity and mortality and are the leading cause of technique failure and transfer from PD to HD. The two predominant infectious complications are peritonitis and catheter-related infections, which include both exit-site and tunnel infections.

TABLE 30-9 Medical Complications of Peritoneal Dialysis



Images The incidence of peritonitis is influenced by connector technology, by the composition of patient populations, and by the use of APD versus CAPD. The incidence of peritonitis reported by most dialysis centers in the United States is about one episode every 24 patient-months, although it may be as low as one episode every 60 patient-months.123 Within 1 year of starting CAPD, 40% to 60% of patients develop their first episode of peritonitis (although the incidence is significantly lower in APD patients).

CLINICAL PRESENTATION Peritoneal Dialysis-Related Peritonitis


    • Patients generally present with abdominal pain and cloudy effluent


    • The patient may complain of abdominal tenderness, abdominal pain, fever, nausea and vomiting, and chills


    • Cloudy dialysate effluent may be observed

    • Temperature may or may not be elevated

Laboratory Tests

    • Dialysate white blood cell count >100/mm3 (>108/L), of which at least 50% are polymorphonuclear neutrophils

    • Gram stain of a centrifuged dialysate specimen

Other Diagnostic Tests

    • Culture and sensitivity of dialysate should be obtained

Clinical Presentation Peritonitis is a major cause of catheter loss in PD patients. A statistically significant correlation between infectious complications and death rates has been reported. Of patients who had more than 1 peritonitis episode per year, 0.5 to 1 episode per year, or less than 0.5 episode per year, 50% died after 3, 4, and 5 years of therapy, respectively. It is important to note that these relationships are not necessarily cause and effect, as many of these patients succumb to cardiovascular events.124

Peritonitis has several imprecise definitions, but guidelines suggest that an elevated dialysate white blood cell count of greater than 100 per microliter (or 108/L) with at least 50% polymorphonuclear neutrophils indicates the presence of inflammation, of which peritonitis is the most likely cause. The patient who presents with abdominal pain and a cloudy effluent is usually given a provisional diagnosis of peritonitis. Inherent in this definition is a number of false-positive and false-negative diagnoses, because a small percentage of patients with culture-proven peritonitis will have clear dialysate, and some patients, such as menstruating females, may have cloudy PD effluent without clinical infection. Sterile culture peritonitis remains problematic; it is defined as an episode in which there is clinical suspicion of peritonitis, but for which the culture of the dialysate reveals no organism. There are several postulates for the high incidence (up to 20% of episodes) of culture-negative peritonitis. Many peritonitis-producing organisms are slime producers and may adhere to the peritoneal membrane or to the catheter surface and be protected from exogenous antibiotics. Sufficient numbers of these bacteria may proliferate to cause peritoneal membrane inflammation and clinical peritonitis, but an inadequate number may seed into the peritoneal cavity to be recovered by conventional microbiologic techniques. In addition, free-floating planktonic bacteria may be rapidly phagocytosed by peritoneal white blood cells, thereby rendering them unavailable for culture.125

Contemporary methods have increased the recovery rate of organisms and decreased the culture-negative rate. Centrifugation is currently recommended as the optimum culture method. Centrifugation of a large volume of dialysate (50 mL), resuspension of the sediment in 3 to 5 mL of sterile saline, and subsequent inoculation in culture media produce a culture-negative rate less than 5%. If centrifuge equipment is not available, blood culture bottles can be directly injected with 5 to 10 mL of dialysate effluent. However, this method results in a culture-negative rate of up to 20%.126

The majority of infections are caused by gram-positive bacteria, of which Staphylococcus epidermidis is the predominant organism. There is no single predominant gram-negative organism. Together, gram-positive and gram-negative organisms account for 80% to 90% of all episodes of peritonitis, and constitute the spectrum against which initial empiric therapy is directed.127

Catheter-Related Infections

PD patients experience an exit-site infection approximately once every 24 to 48 months. Patients with previous infections tend to have a higher subsequent incidence. The majority of exit-site infections are caused by S. aureus. In contrast to peritonitis, S. epidermidis accounts for less than 20% of exit-site infections. Although gram-negative organisms, such as Pseudomonas, are less common, they can result in significant morbidity. The diagnostic characteristics of these infections are somewhat vague but generally include the presence of purulent drainage, with or without erythema at the catheter exit site. The risk of exit-site infections is increased several-fold in patients who are nasal carriers of S. aureus.128

Management of Infectious Complications


The International Society of Peritoneal Dialysis (ISPD) updated the PD-related infections recommendations in 2010, which provide guidelines for treatments such as peritonitis, tunneled, and exit-site infections. These PD-related infections are associated with dialysis modality treatment failures and substantial morbidity and mortality; therefore, appropriate pharmacotherapy treatment is essential (Fig. 30-4).126 The ISDP guidelines specifically address the importance of dialysis center-specific antibiotic selection, the effect of RRF on antibiotic pharmacokinetics, and updated recommendations regarding the use of aminoglycosides and vancomycin in PD patients. In 2011, ISPD published a position statement on reducing the risks of PD-related infections.129 The ISPD position statement includes updates to the prevention of exit-site infections and routine care for PD patients.


FIGURE 30-4 Pharmacotherapy recommendations for the treatment of bacterial peritonitis in PD patients. aChoice of empiric treatment should be made based on the dialysis center’s and the patient’s history of infecting organisms and their sensitivities. bFinal choice of therapy should always be guided by culture and sensitivity results. (MRSA, methicillin-resistant Staphylococcus aureus; MRSE, methicillin-resistant Staphylococcus epidermidis;S. aureusStaphylococcus aureus;S. epidermidisStaphylococcus epidermidis; VRE, vancomycin-resistant enterococci; WBC, white blood cell.)

IP administration of antibiotics remains the preferred delivery route over IV therapy. Antimicrobial dosing recommendations provided in the ISPD guidelines distinguish between dosing for intermittent (one exchange per day) and continuous therapy (all exchanges). In addition, dosing recommendations are modified on the basis of the patient’s PD modality (CAPD or APD) and whether the patient has RRF (urine output) >100 mL/day.126,129

Following a single IP antibiotic dose the drug concentrations achieved in dialysate and serum differ between intermittent and continuous methods. Intermittent therapy IP therapy necessitates that sufficient drug concentration transfers from the peritoneal cavity to systemic circulation thus allowing drug to diffuse back into the peritoneum during drug-free dialysate dwell time(s). Therefore, once daily dosing requires drug(s) be added to the exchange with the longest dwell time to ensure maximum bioavailability.

Continuous dosing recommendations may indicate the need for a loading dose with the very first IP dose with a maintenance dose for each subsequent exchange. Vancomycin, aminoglycoside, and cephalosporin agents generally can use either drug dosing method. It is recommended that a continuous dosing method be used for penicillins and fluoroquinolones. No matter which CAPD drug dosing method is used the goal is to deliver and maintain adequate peritoneum drug concentrations. Intermittent or continuous dosing is effective for CAPD patients but IP dosing for APD patients may require a different dosing schedule. The rapid overnight dialysate exchanges with APD will increase solute clearance over a short time period. This appears to be particularly important for first generation cephalosporin agents. The ISPD guidelines recommend continuous dosing of a first-generation cephalosporin because of concerns over inadequate IP drug concentration during the shorter APD dialysate dwells. Another consideration would be to switch a patient to a CAPD regimen until treatment for peritonitis is completed. With regard to RRF, in patients with daily urine output greater than 100 mL, the dose should be empirically increased by 25% for drugs that are renally eliminated. The ISPD dosing recommendations for IP antibiotics in CAPD and APD patients are shown in Tables 30-10 and 30-11, respectively.126

TABLE 30-10 Intraperitoneal Antibiotic Dosing Recommendations for Continuous Ambulatory Peritoneal Dialysis Patients126


TABLE 30-11 Intermittent Intraperitoneal Antibiotic Dosing Recommendations for Automated Peritoneal Dialysis Patients126


The compatibility and stability of antibiotics added to peritoneal dialysate is another important consideration. In dextrose solutions, most antibiotic additives appear to be stable (usually defined as retaining at least 90% of initial activity) for about 1 week if refrigerated, or 1 to 2 days if left at room temperature. Recent data suggest that cefazolin, ceftazidime, cefepime, vancomycin, gentamicin, tobramycin, netilmicin, and heparin are stable in icodextrin.130132 A concern with some compatibility and stability studies is that an assay of total drug concentration may include parent drug-degradation products in addition to active drug; therefore, the solution may not retain sufficient pharmacologic activity.

The systemic toxicities of IP regimens remain unclear, but are likely similar to those associated with IV and oral antibiotic administration. Intermittent (once-daily) IP dosing of drugs, such as aminoglycosides, may reduce the risk of systemic toxicity (ototoxicity and nephrotoxicity).126 Due to controversial/conflicting clinical trial data,133,134 the current ISPD guidelines state that there is no convincing evidence that short courses of aminoglycosides lead to loss of RRF. Also, that prolonged or repeated courses are probably inadvisable if an alternative approach is available.127 This latter controversial recommendation was based on the opinion of the committee and restated in a recent NKF-K/DOQI document. Since the preservation of RRF is very important for PD patients, routine use of aminoglycosides should be avoided in patients with significant RRF (producing >100 mL urine per day) if other antibiotic choices are available.126

Clinical Controversy…

The ISPD guidelines for peritonitis treatment state that patients with significant RRF should not receive aminoglycosides if other antibiotic choices are available. Aminoglycosides were found to increase the rate of decline in RRF in one study. However, another study refuted this claim.

Initial empiric therapy for peritonitis, regardless of whether a Gram stain was performed or organisms were identified, should include agents effective against both gram-positive and gram-negative organisms. Antibiotic selection should be based on a dialysis center’s antibiogram or resistance patterns, a history of the patient’s infections, and the organism’s antibiotic sensitivity profile. In many cases, a first-generation cephalosporin such as cefazolin in combination with a second drug that provides broader gram-negative coverage, such as ceftazidime, cefepime, or an aminoglycoside, will prove suitable. Patients with documented allergy to cephalosporin antibiotics can be treated with vancomycin and an aminoglycoside. High rates of methicillin resistance have been reported by many dialysis centers and vancomycin should be used as first-line therapy against gram-positive organisms for patients treated at these centers. Monotherapy with agents providing both gram-positive and gram-negative coverage is an alternative option. Both imipenem–cilastatin and cefepime are effective in treating CAPD-related peritonitis.135

After culture and sensitivity results are obtained, antibiotic therapy should be adjusted appropriately (see Fig. 30-4). Tables 30-10 and 30-11 list doses for antibiotics. Treatment should be continued for 14 to 21 days. If the patient does not show a sign of clinical improvement within 72 hours after antibiotic treatment is initiated, the culture should be repeated and the patient reevaluated. If the peritoneal dialysate white blood cell count remains high after 4 days of appropriate antibiotic therapy, clinicians should consider removing the peritoneal catheter, starting IV antibiotics and initiating HD for dialytic maintenance therapy.

Fungal peritonitis is associated with a poor prognosis and high morbidity and mortality. One problem with prospective assessment of antifungal regimens is the infrequency with which these infections occur. This makes it difficult to design and implement comparative studies. Most literature about antifungal treatment is therefore retrospective or limited to reports of local experience.136 As a result, the ISPD recommendations for treatment of fungal peritonitis are somewhat vague and treatment should be based on culture and sensitivity results. However, one area that has been clarified is the question as to whether the PD catheter should be removed. The ISPD recommendations are to remove the catheter immediately after identifying fungi. If the Gram stain indicates the presence of yeast, treatment may be initiated with amphotericin B and oral flucytosine. Once culture and sensitivity results are available, fluconazole, caspofungin, or voriconazole may replace amphotericin B. Treatment with these agents should be continued orally for an additional 10 days after catheter removal. It remains unclear whether there is any benefit from fungal prophylaxis.137 Recommendations are also provided for the treatment of mycobacterial, or tuberculous, peritonitis. Although this infection is a rare complication, it can be difficult to diagnose, and treatment requires multiple drugs.

Catheter-Site Infections

Topical antibiotics and disinfectants appear to be effective agents for the prevention of exit-site infections.138141 Gram-positive organisms should be treated with oral penicillinase-resistant penicillin or a first-generation cephalosporin such as cephalexin (Fig. 30-5). Rifampin may be added if necessary, in slowly resolving or particularly severe S. aureus infections. Vancomycin should be avoided in routine or empiric treatment of gram-positive catheter-related infections, but will be necessary for MRSA. Gram-negative organisms should be treated with oral quinolones. The effectiveness of oral quinolones may be diminished owing to the chelation drug interactions with divalent and trivalent metal ions, which are commonly taken by dialysis patients. Administration of quinolones should occur at least 2 hours prior to these drugs. In cases where Pseudomonas aeruginosa is the pathogen, a second antipseudomonal drug should be added. IP ceftazidime may be considered. In all cases antibiotics should be continued until the exit site appears normal; 2 to 3 weeks of therapy may be necessary. A patient with a catheter-related infection that progresses to peritonitis will usually require catheter removal.126,129


FIGURE 30-5 Management strategy of exit-site infections for PD patients. IP, intraperitoneal; PO, orally. (From reference 128.)

Prevention of Peritonitis and Catheter Exit-Site Infections

Images Attempts to prevent peritonitis and catheter-related infections have included refinement of connector system technology (Luer-Lok connectors), enhanced patient training techniques, and the use of prophylactic antibiotic regimens and vaccines.142 Several studies have examined the impact of antibacterial agents as prophylaxis against both peritonitis and tunnel-related infections. Intermittent rifampin, 300 mg orally twice a day for 5 days, repeated every 3 months, appears to decrease the number of catheter-related infections, but not the incidence of peritonitis. The efficacy of other antibiotic prophylaxis for peritonitis and catheter-related infections is limited. Long-term, extended-duration prophylaxis with penicillins or cephalosporins is not effective.126,129

Nasal carriage of S. aureus is associated with an increased risk of catheter-related infections and peritonitis.126,129 In addition, diabetic patients and those on immunosuppressive therapy are at increased risk for S. aureus catheter infections. Prophylaxis with intranasal mupirocin (twice daily for 5 to 7 days every month), mupirocin (daily) at the exit site, or oral rifampin can effectively reduce S. aureus exit-site infections. Because of the minimal toxicity of mupirocin and the risk of rifampin resistance, mupirocin regimens are preferred.126,129 However, it is important to note that S. aureus isolates with a high degree of resistance to mupirocin have been isolated from PD patients using prophylactic mupirocin at the peritoneal catheter exit site.143 However, a recent study did not observe resistance patterns with the use of mupirocin. Patients in this study applied mupirocin to the exit-site either once or thrice weekly. After three years exit-site infections and peritonitis rates were significantly lower in the thrice weekly application group.144 In addition, gentamicin cream applied daily to the exit site has been found to effectively reduce both S. aureus and P. aeruginosa exit-site infection,126,129 but a recent study comparing mupirocin 2% and gentamicin 0.1% creams for exit-site prophylaxis noted a decrease in gentamicin susceptibility patterns for Enterobacteriaceace(12%) and Pseudomonas (14%).145

A double-blinded, randomized controlled trial compared the use of the topical ointments mupirocin to polysporin triple (P3; bacitracin, gramicidin, and polymyxin B) in PD patients (n = 201) for the prevention of PD-related infections. Patients applied the ointment to the exit site with each dressing change and were followed for up to 18 months. No significant difference was found between groups for time to first PD-related infections (P = 0.41) for either agent, but a significant increase in fungal infections was observed in the P3 versus mupirocin group (7 vs. 0; P = 0.01). The authors concluded that the use of P3 for PD-related infection prophylaxis was not superior to mupirocin and may increase the risk of fungal infections.146


Because of the limitation of available kidneys for transplantation, dialysis (HD and PD) remains the most widely available and commonly used ESRD treatments. Despite continual advances in dialysis and transplantation, kidney disease is associated with significant morbidity and mortality. Given the lack of a true cure for CKD, emphasis recently has been placed on the prevention and early detection of kidney disease. Goals set by the NKF-K/DOQI, the Healthy People 2010 initiative, and the Centers for Medicare and Medicaid Services’ CPM Project provide guidance and direction for all healthcare practitioners. In fact, there have been some significant gains in recent years in terms of incidence rate of ESRD, optimal access placement, and mortality and morbidity.45,147 For patients with ESRD, a focus on quality of life and rehabilitation may be a valuable and viable goal toward which the nephrology community should direct its research resources. Although prevention of ESRD is the primary goal for clinicians and adequate access to renal transplantation is secondary, dialysis will likely be a part of the treatment paradigm for ESRD for many years to come.


The authors wish to acknowledge the contributions of Rowland Ewell, Pharm. D., Edward F. Foote, Pharm. D., and Harold J. Manley, Pharm. D., to the previous editions of this chapter.




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