Article

New solutions for peritoneal dialysis in adult and pediatric patients.

Renal Division, Baxter Healthcare, McGaw Park, Illinois, USA.
Peritoneal dialysis international: journal of the International Society for Peritoneal Dialysis (Impact Factor: 2.2). 02/1999; 19 Suppl 2:S429-34.
Source: PubMed

ABSTRACT The standard PD solutions used today contain physiological electrolyte profiles similar to that of interstitial fluids and are supplemented with glucose as the osmotic agent. Improvements in solution composition during the last 20 years have been largely restricted to minor changes in buffer and electrolyte levels. Newer PD solutions, on the other hand, are designed to manage comorbidities associated with patients on maintenance dialysis, to tailor the ultrafiltration profile based upon dwell time, and to better preserve peritoneal membrane function and host defenses. The evidence to date indicates that, in malnourished PD patients (children and adults), IP amino acids improve protein nutritional status, particularly if low protein intakes are a cause of the malnutrition. The availability of glucose polymers allows the clinician to complement standard glucose-based formulations with one that can provide improved ultrafiltration in both CAPD and APD patients for long dwells, and in patients experiencing ultrafiltration loss owing to a large effective peritoneal surface area. Owing to the reduced calorie and carbohydrate load, glucose polymers may also offer long-term metabolic advantages. Although the control of acid-base balance can be well managed in the vast majority of patients with a 35-40 mmol/L lactate solution, the development and clinical evaluation of bicarbonate-based solutions is underway as a result of concern over the potentially bioincompatible nature of acidic lactate formulations. To date, in vitro, ex vivo, and limited clinical studies show that such formulations, and in particular bicarbonate/lactate combinations are efficacious and well tolerated, and show improved peritoneal cell function versus conventional solutions. In conclusion, ongoing research and development has produced a new generation of PD solutions that, to various degrees, meet different criteria established for an ideal PD solution for chronic adult and pediatric patients on PD. These criteria include good clearance and ultrafiltration, supply of nutrition, iso-osmolality, physiologic pH, bicarbonate buffer, and minimal absorption of the osmotic agent. Several of the new solutions have already demonstrated clinical utility in controlled clinical trials and are commercially available in Europe. Wider clinical use will further add to our understanding of the impact of these formulations on patient outcomes.

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    ABSTRACT: Icodextrin (Extraneal) is a high molecular weight glucose polymer developed specifically for use as an alternative osmotic agent to dextrose during the once-daily long-dwell exchange in peritoneal dialysis (PD). Isosmotic 7.5% icodextrin solution induces transcapillary ultrafiltration (UF) by a mechanism resembling 'colloid' osmosis (unlike hyper-osmolar dextrose-based solutions, which induce UF by crystalline osmosis). In addition, absorption of icodextrin from the peritoneal cavity is relatively slow compared with that of dextrose; this results not only in UF of longer duration, but also a lower carbohydrate load compared with medium (2.5%) and strong (4.25%) dextrose exchanges. In randomised clinical trials of up to 2 years in duration, administration of icodextrin for the long (8- to 16-hour) overnight exchange in continuous ambulatory peritoneal dialysis (CAPD) or daytime exchange in automated peritoneal dialysis (APD) produced net UF which exceeded that with 1.5% and 2.5% dextrose solutions (thereby improving fluid balance), and was equivalent to that with 4.25% dextrose solution. Icodextrin also increased peritoneal clearances of creatinine and urea nitrogen compared with 2.5% dextrose solution. The increase in UF volume with icodextrin was enhanced in CAPD patients with high peritoneal membrane permeability (i.e. high and high-average transporters), maintained in the small number of patients followed-up for 2 years and sustained during episodes of peritonitis. Icodextrin reduced the percentage of patients with net negative UF in contrast to 1.5% and 2.5% dextrose and, in noncomparative studies, extended PD technique survival in patients who had failed dextrose-based dialysis. The use of icodextrin was also associated with some symptomatic improvements and health-related quality of life advantages, and no adverse effect on patient survival, compared with dextrose, although confirmation of these findings is ideally required in appropriately designed studies. The tolerability of icodextrin was generally similar to that of dextrose-based solutions in controlled clinical trials, although there was an approximate three-fold increase in the risk of new skin rash (5.5% vs 1.7%). However, reports of severe cutaneous hypersensitivity reactions remain rare; this possibility should not preclude the use of the polymer. CONCLUSION: 7.5% icodextrin solution offers the first feasible alternative to conventional dextrose solutions for the once-daily long-dwell exchange in PD. It is effective, generally well tolerated and appears to be most useful in situations of reduced or inadequate UF with dextrose, including in high and high-average transporters, during episodes of peritonitis and patients who have failed dextrose-based dialysis.
    Drugs 02/2003; 63(19):2079-105. · 4.13 Impact Factor
  • Article: Icodextrin
    [Show abstract] [Hide abstract]
    ABSTRACT: Icodextrin (Extraneal®) is a high molecular weight glucose polymer developed specifically for use as an alternative osmotic agent to dextrose during the once-daily long-dwell exchange in peritoneal dialysis (PD). Isosmotic 7.5% icodextrin solution induces transcapillary ultrafiltration (UF) by a mechanism resembling ‘colloid’ osmosis (unlike hyper-osmolar dextrose-based solutions, which induce UF by crystalline osmosis). In addition, absorption of icodextrin from the peritoneal cavity is relatively slow compared with that of dextrose; this results not only in UF of longer duration, but also a lower carbohydrate load compared with medium (2.5%) and strong (4.25%) dextrose exchanges. In randomised clinical trials of up to 2 years in duration, administration of icodextrin for the long (8- to 16-hour) overnight exchange in continuous ambulatory peritoneal dialysis (CAPD) or daytime exchange in automated peritoneal dialysis (APD) produced net UF which exceeded that with 1.5% and 2.5% dextrose solutions (thereby improving fluid balance), and was equivalent to that with 4.25% dextrose solution. Icodextrin also increased peritoneal clearances of creatinine and urea nitrogen compared with 2.5% dextrose solution. The increase in UF volume with icodextrin was enhanced in CAPD patients with high peritoneal membrane permeability (i.e. high and high-average transporters), maintained in the small number of patients followed-up for 2 years and sustained during episodes of peritonitis. Icodextrin reduced the percentage of patients with net negative UF in contrast to 1.5% and 2.5% dextrose and, in noncomparative studies, extended PD technique survival in patients who had failed dextrose-based dialysis. The use of icodextrin was also associated with some symptomatic improvements and health-related quality of life advantages, and no adverse effect on patient survival, compared with dextrose, although confirmation of these findings is ideally required in appropriately designed studies. The tolerability of icodextrin was generally similar to that of dextrose-based solutions in controlled clinical trials, although there was an approximate three-fold increase in the risk of new skin rash (5.5% vs 1.7%). However, reports of severe cutaneous hypersensitivity reactions remain rare; this possibility should not preclude the use of the polymer. Conclusion: 7.5% icodextrin solution offers the first feasible alternative to conventional dextrose solutions for the once-daily long-dwell exchange in PD. It is effective, generally well tolerated and appears to be most useful in situations of reduced or inadequate UF with dextrose, including in high and high-average transporters, during episodes of peritonitis and patients who have failed dextrose-based dialysis. Pharmacodynamic Properties Icodextrin, a starch-derived, water-soluble, glucose polymer (average molecular weight 16.8kDa) linked predominantly by α1–4 glucosidic bonds, induces trans-capillary ultrafiltration (UF; removal of excess fluid from the plasma) by a mechanism resembling ‘colloid’ osmosis. Thus, icodextrin-based peritoneal dialysis (PD) solutions can be iso-osmotic with respect to normal plasma, unlike hyper-osmotic dextrose-based solutions, which produce UF by crystalline osmosis. Intraperitoneal administration of PD solution containing 7.5% icodextrin provides sustained UF throughout the once-daily long-dwell exchange (8–16 hours) in patients treated with continuous ambulatory peritoneal dialysis (CAPD) or automated peritoneal dialysis (APD); the effect on UF is immediate with the first exchange. UF volumes with icodextrin are equivalent to those with ‘strong’ (4.25%) dextrose solutions; compared with ‘weak’ (1.5%) and ‘medium’ (2.5%) dextrose solutions, icodextrin increases UF and improves fluid balance. Interestingly, in a 4-month randomised multicentre trial, treatment with icodextrin, but not 1.5% dextrose, was associated with a significant 5% reduction in left ventricular hypertrophy, an effect that was unrelated to changes in volume status or blood pressure. Due to the relatively slow rate of absorption of icodextrin from the peritoneal cavity (which accounts for the prolonged UF effect) the carbohydrate load per exchange is lower than that with 2.5% and 4.25% dextrose solutions. Beneficial effects of icodextrin on insulin sensitivity and plasma lipids (significant reductions in total and low-density lipoprotein cholesterol levels) compared with dextrose have also been observed in some studies. These reports notwithstanding, the incidences of hyperglycaemia (5% vs 4%) and hypercholesterolaemia (2% vs 2%) were similar for icodextrin and dextrose in a pooled analysis of data from controlled clinical trials. Preclinical data suggesting that icodextrin may be a more biocompatible osmotic agent than dextrose have recently received some clinical support. Specifically, icodextrin appeared to have a less deleterious effect on membrane function, especially compared with 2.5% and 4.25% dextrose, in a 2-year prospective study in 177 anuric APD patients. However, neither icodextrin nor 1.5–4.25% dextrose solutions had clinically meaningful effects on peritoneal membrane characteristics during 1–2 years of treatment in randomised studies of nonanuric CAPD patients. Pharmacokinetic Properties Icodextrin is absorbed at a constant rate from the peritoneal cavity, mostly via lymphatic pathways. The amount of icodextrin absorbed thus depends on the dwell time; it represents approximately 40% of the administered dose after a 12-hour exchange. Up to 80% of the absorbed icodextrin dose is eventually metabolised, first by circulating α-amylases and then by tissue maltases, into glucose; the remaining 20% is eliminated via the urine (in direct proportion to the level of residual renal function) or in the dialysate. The plasma profile of icodextrin and its three main metabolites (maltose, maltotriose, and maltotetraose) fits a simple one-compartment model assuming zero-order absorption and first-order elimination. Peak plasma concentrations are reached at the end of a 12-hour dwell and decline to baseline levels within 3–7 days following a single icodextrin exchange. Concentrations of the main icodextrin metabolites in the dialysate also rise during the dwell, either as a result of diffusion from the plasma (maltose) or intraperitoneal metabolism of other, minor metabolites (in the case of maltotriose and maltotetraose), although this has no effect on the osmolality of the solution. The steady-state plasma concentration of icodextrin plus its main metabolites (typically 5–6 g/L) is reached within 7–10 days, with the metabolites accounting for approximately 40% of the total measured polymers. Maltose accumulation is avoided by limiting the use of icodextrin to the once-daily long-dwell exchange. Therapeutic Efficacy The effects of 7.5% icodextrin solution used once daily for the long-dwell exchange in PD have been compared with those of standard dextrose solutions in several clinical trials of up to 2 years in length. These trials include four pivotal, multicentre, randomised studies: three (versus 1.5% and 4.25% dextrose in CAPD [n = 209], 2.5% dextrose in CAPD [n = 175] and 2.5% dextrose in APD [n = 39]) evaluating the short-term (≤6 months) UF efficacy of icodextrin; and one (versus 2.5% dextrose in CAPD or APD [n = 278]) assessing the long-term (1-year) effects of the polymer on patient survival and health-related quality of life (HR-QOL). The effects of icodextrin on UF and small solute (e.g. creatinine, urea nitrogen) clearances were broadly similar when administered for the long overnight exchange (8–16 hours) in patients undergoing CAPD or the long daytime exchange (12–16 hours) in patients receiving APD. The increase in UF volume with icodextrin was maintained in a small number of patients (12 CAPD, 7 APD) foliowed-up for 2 years and preserved during episodes of peritonitis. Net UF during the long-dwell exchange with icodextrin was significantly greater than that with 1.5% and 2.5% dextrose solutions, and was similar to that with 4.25% dextrose solution. Icodextrin also reduced the percentage of patients with net negative UF in contrast to 1.5% and 2.5% dextrose. In a double-blind study in 175 patients undergoing CAPD, the average net UF during the 1-month treatment period was 1.7 times higher with icodextrin than with 2.5% dextrose (587 vs 356mL; p < 0.001); the greatest relative benefit with icodextrin was seen in high and high-average transporters. In addition, the average peritoneal clearances of creatinine and urea nitrogen were 1.1 times higher with icodextrin than with 2.5% dextrose (4 vs 3.5 mL/min and 4.5 vs 4.1 mL/min, respectively; p ≤ 0.001). Available data suggest that CAPD patients receiving icodextrin for 6–12 months experience some symptomatic improvements and HR-QOL advantages compared with those receiving dextrose. Overall, perceived HR-QOL declined in a double-blind study in 278 patients receiving CAPD or APD, although the deterioration was less in patients treated with icodextrin, with 30% considering themselves to be much better now than 1 year ago compared with only 4% of those receiving 2.5% dextrose (p < 0.05). Similarly, available data suggest that treatment with icodextrin does not, on the whole, adversely affect patient survival and, furthermore, may extend PD technique survival in patients with UF failure who are on the point of transferring to haemodialysis. Tolerability Pooled data from controlled clinical trials (n = 840) suggest that, while in general icodextrin is as well tolerated as conventional dextrose-based solutions, it is three times more likely to cause new skin rash (5.5% vs 1.7%). A total of 265 patients were randomised to icodextrin in two pivotal multicentre, randomised, double-blind studies conducted in North America; of these, eight (3%) discontinued the polymer because of rash or exfoliative dermatitis. There have also been several reports of serious cutaneous hypersensitivity reactions occurring in clinical practice, although these remain rare overall. Pharmacovigilance data provided by the manufacturer suggest that most skin eruptions (incidence rate ≈2.5%) are mild, while more than half are self-limiting. Use of icodextrin was not associated with an increased frequency of peritonitis or exit-site infections in large-scale clinical trials. There have, however, been several reports of icodextrin-associated aseptic peritonitis attributed to contamination of some batches of the manufactured product with peptidoglycan. Body weight was little changed during 6–12 months of treatment with icodextrin or dextrose, with the notable exception of a significant (p < 0.05) 2.3kg increase with dextrose in the 1-year double-blind study in 278 patients receiving CAPD or APD. Overall, oedema occurred with a similar frequency in patients treated with icodextrin or dextrose in controlled clinical trials (6% vs 5%). Slight decreases in plasma sodium and chloride levels are attributed to a dilutional effect of icodextrin metabolites in the plasma, as are small increases in osmolality and alkaline phosphatase levels. However, these laboratory changes are not clinically significant. Dosage and Administration PD solution containing 7.5% icodextrin is indicated as a single daily exchange for the long (8- to 16-hour) dwell during CAPD or APD for the management of end-stage renal failure. It is contraindicated, however, in patients with a known allergy to cornstarch and those with glycogen storage disease. Patients and physicians should follow all the normal procedures and precautions regarding intraperitoneal administration of dialysis solutions. In particular, not more than one long-dwell icodextrin exchange should be performed in a 24-hour period. Importantly, plasma glucose levels in insulin-dependent diabetic PD patients must be measured using glucose-specific tests to avoid interference by icodextrin and its metabolites (resulting in erroneously high estimates of glycaemia). Icodextrin and its metabolites also interfere with enzymatic-based plasma amylase activity assays (resulting in inaccurately low values).
    Drugs 10/2003; 63(19):2079-2105. DOI:10.2165/00003495-200363190-00011 · 4.13 Impact Factor
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    ABSTRACT: In the present study, we surveyed 425 members of the American Pediatric Surgical Association and the Canadian Association of Pediatric Surgeons to identify prevalent operative techniques used in the placement of peritoneal dialysis catheters by pediatric surgeons. Our survey assessed catheter type, skin and fascial incision orientations, deep-cuff positions, exit-site directions, and omentectomy. We received responses from 156 surgeons (36.7%) and excluded 18 of those responses. Among the assessed responses, 83 surgeons (60%) indicated that they had placed at least 1 catheter in the previous 12 months. Of the 83, 13% had placed 1 catheter, 52% had placed 2 - 5, 16% had placed 6 - 9, and 18% had placed 10+. We observed significant variability in all aspects of surgical technique. The most common catheter configuration was single-cuff (59%), curled end (60%), and non swan neck (72%). The most common surgical approach was a transverse skin incision (52%), a fascial incision through the rectus (68%), a deep cuff between the peritoneum and fascia (46%), a superior-pointing exit site (37%), and a superficial cuff distant to the exit site (53%). Routine omentectomy was reported by 59% of respondents. Only 15% reported using a laparoscopic approach on first attempt. Pediatric surgeons employ a variety of surgical techniques when placing peritoneal catheters. Some of the techniques used vary from the published recommendations. Quality can potentially be improved by wider dissemination of published surgical recommendations.
    Advances in peritoneal dialysis. Conference on Peritoneal Dialysis 02/2004; 20:218-21.
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