The effect of regional transmural agreements on the information transfer of frail older patients.

INTRODUCTION: Frail older patients are at risk for many complications when admitted to the hospital. Multidisciplinary regional transmural agreements (RTA) in which guidelines were set concerning the information transfer of frail older patients might improve outcomes. We aim to investigate the effect of implementation of the RTA on the completeness of the information transfer of frail older patients when admitted to and discharged from the hospital. METHODS: This is a retrospective cohort study in which we collected data from 400 randomly selected hospitalized frail older patients (70+) before the implementation of the RTA, January through March 2021, and after, October through December 2021. The cohort was split up into four groups, which determined what correspondence would be checked (referral letter by General Practitioner (GP) and three groups of 'hospital letters': ED letter upon admittance, clinical discharge letter to the elderly care physician and clinical discharge letter to the GP. We assessed for mention of frailty, a medication list and mention of resuscitation orders. RESULTS: In the period before implementation the mean age of patients was 82.6 years (SD 7.4) and 101 were female (50.5%), after implementation mean age was 82.3 (SD 6.9) and 112 were female (56.0%). Frailty was mentioned in hospital letters in 12.7% before and 15.3% after implementation (p = 0.09). More GP referral letters were present after implementation (32.0% vs. 54.0%, p = 0.03), however frailty was mentioned only in 12.5% before and 7.4% after (p = 0.58). There was a good handover of medication lists from the hospital (89.3% before, 94% after, p = 0.20) and even better from the GP (93.8% before, 100% after, p = 0.19). Resuscitation orders were mentioned in 59.3% of letters from the hospital before implementation and 57.3% after (p = 0.77), which is higher than in the referral letters (18.8% before and 22.2% after (p = 0.91). DISCUSSION: The implementation of RTA improved the number of GP referral letters present; however, it did not lead to other significant improvements in communication between the hospital and the GP's. Frailty and resuscitation orders are still frequently not mentioned in the reports. After a successful reimplementation, the improvements of outcomes could be investigated.

A Dutch consensus statement on the diagnosis and treatment of ANCA-associated vasculitis.

INTRODUCTION: Despite the availability of several guidelines on the diagnosis and treatment of antineutrophil cytoplasmic antibody-associated vasculitis (AAV), clinical routine practice will only improve when an implementation strategy is in place to support clinical decision making and adequate implementation of guidelines. We describe here an initiative to establish national and multidisciplinary consensus on broad aspects of the diagnosis and treatment of AAV relevant to daily clinical practice in the Netherlands. METHODS: A multidisciplinary working group of physicians in the Netherlands with expertise on AAV addressed the broad spectrum of diagnosis, terminology, and immunosuppressive and non-immunosuppressive treatment, including an algorithm for AAV patients. Based on recommendations from (inter)national guidelines, national consensus was established using a Delphi-based method during a conference in conjunction with a nationally distributed online consensus survey. Cut-off for consensus was 70% (dis)agreement. RESULTS: Ninety-eight professionals were involved in the Delphi procedure to assess consensus on 50 statements regarding diagnosis, treatment, and organisation of care for AAV patients. Consensus was achieved for 37/50 statements (74%) in different domains of diagnosis and treatment of AAV including consensus on the treatment algorithm for AAV. CONCLUSION: We present a national, multidisciplinary consensus on a diagnostic strategy and treatment algorithm for AAV patients as part of the implementation of (inter)national guideline-derived recommendations in the Netherlands. Future studies will focus on evaluating local implementation of treatment protocols for AAV, and assessments of current and future clinical practice variation in the care for AAV patients in the Netherlands.

When to start dialysis?

In an attempt to decrease mortality in dialysis patients, the care for end-stage renal disease patients has been a focus of nephrologists for many years. Good pre-dialysis care has been found to improve mortality numbers in several studies. However, it is still not exactly clear, when the best moment has arrived to start renal replacement therapy. By illustrating two totally different patient cases the effect of outcome and quality of life are discussed-demonstrating on the one hand the role of clinical parameters, and on the other hand the influence of biochemical parameters.

Amphotericin B, mercury chloride and peritoneal transport in rabbits.

BACKGROUND: The effect of glucose-induced ultrafiltration in peritoneal dialysis is dependent on the presence and function of ultrasmall transendothelial cell water channels. The mercury-sensitive aquaporin-1 was thought to represent these transcellular pores. Amphotericin B (ampho B) has been reported to increase ultrafiltration in both experimental and patient studies. The objective of this study was to investigate the hypothesis that intraperitoneal ampho B increases and mercury chloride inhibits aquaporin-1-mediated water transport in a chronic peritoneal dialysis model in the rabbit. MATERIAL AND METHODS: Eighteen female New Zealand White rabbits were included for peritoneal catheter implantation. Peritoneal transport parameters were determined in all rabbits by standard peritoneal permeability analysis (SPAR) with 3.86% glucose-based dialysis solution during a one-hour dwell prior the intervention SPARs, as a control. Ampho B (0.06 mg/kg body weight) was added to the dialysate for 3 (n = 9) or 5 consecutive days (n = 5) before investigation. Four rabbits were investigated after 3-day i.p. 0.6 mg/kg body weight ampho B. In 3 rabbits 0.06 mg/kg body weight liposomal ampho B was administered i.p. during 3 days before intervention SPAR. Fifteen rabbits were investigated during a one-hour dwell with 0.1 mM HgCl2 containing 3.86% glucose-based dialysis solution, while they were anesthetized. Three of these underwent in vivo fixation with glutaraldehyde prior to the HgCl2 SPAR to prevent toxic effects of mercury on peritoneal tissues. RESULTS: Intraperitoneal administration of ampho B did enhance the change in intraperitoneal volume during a one-hour dwell after 3-day i.p. treatment with the low dose (p < 0.02), but it did not affect peritoneal solute permeability. This was likely mediated by transcellular water channels, but not by aquaporin-1. No beneficial effects on the ultrafiltration were found with prolonged treatment or with the higher dose. Ultrafiltration decreased (8 ml/4 h to 1 ml/4 h, p < 0.03) after i.p. administration of HgCl2 with and without in vivo fixation, accompanied by a significant decrease in aquaporin-mediated water transport, estimated as the sieving of sodium (p < 0.001). Marked increases in the clearances of macromolecules were found after i.p. HgCl2 administration due to toxic effects: total protein clearance from 97 to 172 microl/min, p < 0.005, and albumin clearance from 59 to 158 microl/min, p < 0.005. These changes were less pronounced after in vivo fixation. CONCLUSION: Ampho B has likely no clinical relevance in treatment of ultrafiltration failure in PD patients. Aquaporin-mediated water transport could be inhibited and consequently ultrafiltration was reduced by i.p. administration of mercury chloride in our rabbit model.

Prostaglandin inhibition by intraperitoneal indomethacin has no effect on peritoneal permeability during stable CAPD.

BACKGROUND: Prostaglandins can affect the vascular response and are locally produced in the peritoneal cavity. Prostaglandin inhibition in continuous ambulatory peritoneal dialysis (CAPD) patients during peritonitis using indomethacin intraperitoneally was found to decrease the intrinsic permeability to macromolecules. METHODS: In the present study the effects of prostaglandin inhibition were studied during stable, uninfected CAPD. Two standard peritoneal permeability analyses (1.36% glucose) were performed in 10 stable CAPD patients within 1 week with and without addition of 12.5 mg/l indomethacin. Furthermore, possible effects on the parameters of nitric oxide synthesis were determined. In five other patients a high dose of indomethacin was tested. The night before the indomethacin test, 12.5 mg/l indomethacin was added to the nightdwell and the test was performed with 25 mg/l indomethacin. RESULTS: In the normal dose indomethacin group, the dialysate concentrations of prostaglandin (PG) 6-keto-PGF1alpha and thromboxane (Tx) TxB2 were significantly lower with indomethacin (IND) compared with the control dwell (C): 6-keto-PGF1alpha median 93 (C) vs 7.5 (IND) ng/l, P=0.006 and TxB2 12.3 (C) vs 9.0 (IND) ng/l, P=0.04. The dialysate concentration of PGE2 was not different during the control dwell (68.5 ng/l) compared with the indomethacin experiment (50.3 ng/l, P=0.5). The mass transfer area coefficients (MTAC) of nitrate and cGMP, and parameters of nitric oxide synthesis, were similar during both experiments. The MTAC of creatinine and urate were not different with indomethacin: creatinine median 9.5 (C) vs 10.2 ml/min (IND), P=0.2 and urate 7.2 (C) vs 7.3 ml/min (IND), P=0.3. Only the MTAC of urea was marginally higher with indomethacin: 16.0 (C) vs 16.6 ml/min (IND), P=0.04. No differences were found in the clearances of the macromolecules beta2-microglobulin, albumin, IgG and alpha2-microglobulin. With the high indomethacin dose no inhibition of PGE2 was found: 69 (C) vs 63 ng/l(IND), not significant. Furthermore, no differences were found in the transport rates of small solutes or proteins. This indicates no effect of indomethacin on the peritoneal surface area and the size-selective permeability to macromolecules. In both groups no effect was found on the transcapillary ultrafiltration and the effective lymphatic absorption rate during the 4-h dwell. Consequently, the net ultrafiltration, the difference between these, did not change. CONCLUSIONS: The indomethacin induced inhibition of the synthesis of 6-keto-PGF1alpha and TxB2 did not lead to alterations in functional parameters of the peritoneal surface area, the intrinsic permeability to macromolecules and fluid kinetics. Therefore, these prostaglandins are not likely to be involved in the regulation of peritoneal transport during stable CAPD.

Nitric oxide-related experiments on peritoneal solute transport in the rabbit.

BACKGROUND: It is unclear whether nitric oxide (NO) is important in regulating peritoneal transport during non-infected peritoneal dialysis. METHODS: In 13 rabbits, 250 mg/l L-arginine, a substrate for NO synthesis, was added to a 3.86% glucose dialysis solution. N:(G)-monomethyl-L-arginine (L-NMMA) 25 mg/1, an inhibitor of NO synthase, was added to the dialysate in 10 rabbits. Standard peritoneal permeability analyses in rabbits were used to analyse the effects of these interventions on solute transport during 1-h dwells. The addition of 4.5 mg/l nitroprusside to the dialysate in five rabbits was used for validation of this model. RESULTS: Nitroprusside caused an 86% (48-233%) increase in albumin clearance, which is similar to the nitroprusside-induced increase found in humans (70%). Contrary to human studies, no effect was found on the mass transfer area coefficient (MTAC) of urea and creatinine, or on glucose absorption. L-Arginine did not affect either the MTAC of urea and creatinine, or the absorption of glucose. Peritoneal albumin clearance increased 18% (-24 to 609%). This resembles the NO-mediated effects of nitroprusside. Addition of L-NMMA caused no change in the solute transport rate. CONCLUSION: The rabbit dialysis model can be used for analysing the effects of interventions on peritoneal permeability characteristics, although the rabbit peritoneal membrane is probably less sensitive to NO compared with that of humans. L-Arginine-induced effects are similar to those of nitroprusside, which suggests that these effects possibly are mediated by NO. As L-NMMA did not affect peritoneal transport, it is unlikely that NO is involved in the regulation of peritoneal permeability in rabbits.

Substrate and inhibitor for nitric oxide synthase during peritoneal dialysis in rabbits.

OBJECTIVE: To investigate the possible influence of nitric oxide (NO) on peritoneal transport during non infected peritoneal dialysis. DESIGN: A chronic peritoneal dialysis model in New Zealand White rabbits (2624 g; range: 2251-3034 g) was used. In 13 rabbits, 250 mg/L L-arginine, a substrate for NO synthesis, was added to 3.86% glucose dialysate. N(G)-monomethyl-L-arginine (L-NMMA) 25 mg/L, an inhibitor of NO synthase, was added to the dialysate in 10 rabbits. Standard peritoneal permeability analyses in rabbits (SPAR) were performed to analyze the effects of these interventions on solute and fluid transport during 1-hour dwells. The addition of 4.5 mg/L nitroprusside to the dialysate in 5 separate experiments was used for validation of this model. MAIN OUTCOME: For the transport of urea and creatinine, mass transfer area coefficients (MTACs) were calculated. Furthermore, the glucose absorption, the peritoneal albumin clearance, peritoneal fluid kinetics, and the dialysate-to-plasma (D/P) ratio of nitrate were calculated. RESULTS: Nitroprusside caused an 86% (48%-233%) increase in albumin clearance, which is similar to the nitroprusside-induced increase found in humans. Contrary to the findings in human studies, no effect was found on the clearances of urea and creatinine, or on peritoneal fluid kinetics. This suggests a lower sensitivity of the rabbit peritoneal membrane for the effect of NO on small-solute transport. L-arginine affected neither the MTACs of urea and creatinine, nor the absorption of glucose. Also, peritoneal fluid kinetics were similar. Peritoneal albumin clearance increased 18% (-24%-609%). This result resembles the NO-mediated effects of nitroprusside. Addition of L-NMMA caused no change in the transport rate of small solutes, in albumin clearance, or in fluid profile. This result suggests that NO synthase is not induced during non infected peritoneal dialysis, which accords with previous studies. CONCLUSION: This rabbit dialysis model can be used for analyzing the effects of interventions on peritoneal permeability characteristics, although the rabbit peritoneal membrane is probably less sensitive to NO compared to that of humans. L-Arginine-induced effects are similar to those of nitroprusside, which suggests that these effects are possibly mediated by NO. Because L-NMMA did not affect peritoneal transport, it is unlikely that NO is involved in the regulation of peritoneal permeability during stable continuous ambulatory peritoneal dialysis.

The standard peritoneal permeability analysis in the rabbit: a longitudinal model for peritoneal dialysis.

OBJECTIVE: The development of an experimental peritoneal dialysis (PD) model in rabbits to investigate peritoneal transport characteristics during a longitudinal follow-up and to assess normal values of these peritoneal transport parameters. DESIGN: Peritoneal transport parameters were determined in conscious, unrestrained rabbits by standard peritoneal permeability analysis adjusted for rabbits (SPAR). In this test a 1-hour dwell with 3.86% glucose dialysate is used. Dextran 70 (1g/L) was added to the dialysate to allow calculation of fluid kinetics. Dialysate samples were taken before, 10, and 40 minutes after instillation and at the end of the dwell. Blood was drawn at the end of the dwell. EXPERIMENTAL ANIMALS: Eighteen female New Zealand White rabbits (2565 g) were included for catheter implantation. SPARs were performed in 15 animals; the other 3 were excluded due to complications. MAIN OUTCOME: The mass transfer area coefficients (MTACs) of the low molecular weight solutes urea (MTAC(urea)) and creatinine (MTACcr) were calculated. The clearances of albumin (CIalb) and IgG (CI(IgG)), glucose absorption, and fluid transport were computed. Coefficients of intraindividual variation (Vc) were calculated for these parameters. RESULTS: The main complications were catheter obstruction and/or dislocation. Five rabbits underwent uncomplicated PD during a 4-week period. Fifteen SPARs in 15 stable rabbits were performed and analyzed to obtain normal values. Means and standard deviations of the transport parameters were as follows: MTAC(urea) 2.24+/-0.57 mL/min, MTACcr 1.61+/-0.30 mU/min, CI(alb) 52.9+/-17.2 microL/min, CI(IgG) 44.5+/-22.9 UL/min. The transcapillary ultrafiltration rate was 0.66+/-0.13 mL/min and the lymphatic absorption rate 0.47+/-0.26 mL/min. The parameters of solute transport were upscaled to those in humans using two different methods. MTACs of low molecular weight solutes in rabbits and patients were of the same order of magnitude, but the clearance of albumin was approximately four times higher in rabbits than in patients, and that of IgG eight times. In all rabbits sieving of sodium was observed. The dialysate/plasma (D/P) of sodium decreased to a minimum at 40 min (p<0.003 vs the initial value), followed by a rise to 60 min. The minimal value was 0.884+/-0.002. The coefficients of variation calculated on 7 rabbits that underwent two or more SPARs were similar to those assessed from the patient data. This indicates stability of the model and reproducibility of the SPAR. CONCLUSION: The conscious rabbit model for PD can be used for repeated studies on peritoneal transport.

Augmenting solute clearance in peritoneal dialysis.

BACKGROUND: The removal of low molecular weight solutes by peritoneal dialysis is less than by hemodialysis. The targets for Kt/Vurea and creatinine clearance formulated in the Dialysis Outcome Quality Initiative are unlikely to be achieved in a substantial portion of peritoneal dialysis patients. Possibilities to increase small solute clearances have therefore been subject to many investigations. METHODS: A review of the literature and of recent new data on determinants of solute removal, such as residual renal function, the role of drained dialysate volume and manipulation of the diffusive capacity of the peritoneum are presented. RESULTS: The contribution of residual GFR is more important for the clearance of creatinine than for Kt/Vurea. It is even more important for the removal of organic acids that are removed from the body by tubular secretion. High dosages of furosemide increase the urinary volume and the fractional Na+ excretion, but have no effect on the magnitude of residual GFR, renal creatinine clearance, renal urea clearance, and peritoneal transport characteristics. The drained dialysate volume per day is the main determinant of the peritoneal removal of urea. Its effect decreases the higher the molecular weight of a solute. It can be augmented by using large instillation volumes, by the application of more exchanges, and by increasing peritoneal ultrafiltration. A large exchange volume is especially effective in patients with an average transport state, but in those with high solute transport rates, Kt/Vurea is especially influenced by the number of exchanges. Possibilities to increase ultrafiltration are discussed. The diffusive capacity of the peritoneum can be augmented by using low dosages of intraperitoneally administered nitroprusside. This increases solute transport most markedly when it is applied in combination with icodextrin as osmotic agent. CONCLUSIONS: Small solutes clearances cannot be increased by furosemide. Increasing the instilled volume of dialysis fluid and the number of exchanges both affect solute clearance. Studies are necessary on long-term effects of manipulation of the peritoneal membrane with nitroprusside.

Are phospholipase A2 and nitric oxide involved in the alterations in peritoneal transport during CAPD peritonitis?

The alterations in peritoneal permeability characteristics during peritonitis can only partly be explained by the increased concentrations of prostaglandins and cytokines in the dialysate. Fifteen patients undergoing continuous ambulatory peritoneal dialysis (CAPD) with 16 peritonitis episodes were examined in the acute phase of the infection by using standard peritoneal permeability analyses (SPAs). In 9 of these patients, a control SPA could be performed. The contribution of nitric oxide (NO), prostaglandins, and the acute phase reactants C-reactive protein (CRP) and secretory phospholipase A2 (sPLA2) were analyzed. The mass transfer area coefficients (MTACs) of low-molecular-weight solutes increased during peritonitis: urea 26%, creatinine 45%, and urate 45%. The MTAC of CO2, calculated to estimate peritoneal blood flow, was 71 mL/min (34 to 254 mL/min) during peritonitis and 55 mL/min (42 to 63 mL/min) after recovery, P < or = .05. The peritoneal protein clearances were also greater during peritonitis, but this increase was not related to the molecular weight of the protein. Therefore the restriction coefficients to macromolecules were not different. The net ultrafiltration in all peritonitis episodes was lower as compared with the control dwells: -97 mL (-196 to 19 mL) versus 25 mL (-132 to 216 mL), P = .03. The prostaglandin concentrations in dialysate were greater during peritonitis than after recovery. The median increase was 199% for prostaglandin E2 (PGE2), 68% for 6-keto-prostaglandin F1alpha (6-keto-PGF1alpha), and 44% for thromboxane B2 (TxB2). Plasma sPLA2 values were 22.7 microg/L (7.3 to 407.6) during peritonitis and 8.9 microg/L (5.5 to 11.5) after recovery, P < .01. The increased plasma sPLA2 during peritonitis correlated with plasma CRP (r = .6; P = .02). The peritoneal clearances of sPLA2 were greater during peritonitis, but this could be attributed completely to the increased peritoneal transport. Both during peritonitis and after recovery, the sPLA2 clearances did not exceed the predicted values based on transport from the circulation to the dialysate. No evidence was found for local production of nitrite or nitrate. However, the MTAC of cyclic guanosine monophosphate (cGMP) was greater during the experiments performed 48 to 72 hours after the onset of peritonitis, which suggests the synthesis of NO. It can be concluded that peritonitis does not induce detectable local release of sPLA2 and that the inflammation-induced increase in the vascular surface area could not be attributed to NO in the acute phase. The activation of inducible NO synthase may occur after 48 hours.

Similarities and differences between the effects of amino acids and nitroprusside on peritoneal permeability during CAPD.

OBJECTIVE: Intraperitoneal administration of amino acid based dialysis solutions affects the surface area available for diffusion, with almost no effect on the intrinsic permeability to macromolecules. Intraperitoneally administered nitroprusside affects the vascular surface area and the intrinsic permeability without effect on the peritoneal blood flow. In the present study, these differences were translated into different effects on the radii of the pores in the peritoneal membrane. METHODS: Effects of amino acid based dialysate and nitroprusside on peritoneal permeability characteristics were evaluated in standard peritoneal permeability analyses with L-arginine-containing amino acid dialysate (10 patients) or with 1.36% glucose dialysate with nitroprusside (10 patients). In each patient a control experiment with 1.36% glucose was performed. Kinetic modeling was done to analyze the effects in terms of the pore theory. RESULTS: Both interventions increased the mass transfer area coefficients of low molecular weight solutes. This is in accordance with an increase in the unrestricted area over diffusion distance found with modeling. With amino acids almost no effect was found on the protein clearances; the increase in the large-pore radius was only small. Nitroprusside induced a marked increase in protein clearances. This was in accordance with an evident increase in the average large-pore radius. CONCLUSIONS: Amino acids affect the radii of the small pores and the large pores to the same extent. Nitroprusside influences especially the large pores. Both amino acids and nitroprusside are vasoactive, although the effects on the peritoneal microcirculation are different.

Icodextrin with nitroprusside increases ultrafiltration and peritoneal transport during long CAPD dwells.

Addition of the nitric oxide (NO) donor nitroprusside to 1.36% glucose dialysate enlarges the effective peritoneal surface area during four-hour dwells. The theoretical positive effect on ultrafiltration is, however, counteracted by an increase in glucose absorption. The absorption of the glucose polymer icodextrin is much lower in comparison with glucose-based dialysis solutions, due to its high molecular weight. In the present study 7.5% icodextrin dialysis solution with and without the addition of 4.5 mg/liter nitroprusside was studied during eight-hour CAPD dwells. Two Standard Peritoneal permeability Analyses, adapted for eight-hour dwells, were performed in 10 stable CAPD patients. Nitrate and cGMP were measured as parameters of NO synthesis. The transcapillary ultrafiltration increased in a linear way with icodextrin (ICO) and was even higher after the addition of nitroprusside (NP): 666 (ICO) versus 834 (NP) ml/8 hr, P = 0.03. The effective lymphatic absorption rate was not different. The resulting net ultrafiltration increased with nitroprusside: 344 (ICO) versus 540 (NP) ml/8 hr, P < 0.01. The mass transfer area coefficient of urea increased 15% and that of creatinine 26% with nitroprusside, consistent with the expected enlargement of the vascular peritoneal surface area. The increase in protein clearances was more pronounced the larger the protein: beta 2-microglobulin 19%, albumin 47%, IgG 63% and alpha 2-macroglobulin 95%. Dialysate/plasma (D/P) ratios of nitrate were not higher than the expected values on the basis of its molecular weight (P < 0.001). They increased 19% with nitroprusside. Also, the D/P ratio cyclic guanosine monophosphate (cGMP) after four hours increased with nitroprusside (0.39, range 0.13 to 0.55 ICO, and 0.82, range 0.36 to 1.39 NP, P = 0.01). With nitroprusside the D/P ratio cGMP was higher than expected after four and eight hours (P < 0.001). This points to local generation of NO after addition of nitroprusside. The nitroprusside induced increase in the mass transfer area coefficients (MTAC) of creatinine and in the ultrafiltration caused an increase in the creatinine clearance from 4.2 ml/min to 5.0 ml/min during the eight-hour dwell. This means that nitroprusside adds 3 liters/week to the peritoneal clearance of creatinine. The adequacy of peritoneal dialysis can therefore be improved by the addition of nitroprusside to 7.5% icodextrin, used for the long exchange.

The nitric oxide donor nitroprusside intraperitoneally affects peritoneal permeability in CAPD.

Nitroprusside is a nitric oxide (NO) donor. To investigate effects of nitroprusside i.p. on peritoneal permeability and perfusion, standard peritoneal permeability analyses were performed. Ten stable CAPD patients were studied twice within one week with glucose based dialysate (1.36% Dianeal) with and without addition of nitroprusside 4.5 mg/liter. Mass transfer area coefficients (MTAC) of CO2 were calculated to estimate peritoneal blood flow. Nitrate, a stable metabolite of NO, and cGMP, a second messenger of NO synthesis, were measured in plasma and dialysate. The MTACs of low molecular weight solutes were greater with nitroprusside (NP) compared to the control dwell (C): creatinine median 14.1 (NP) versus 9.9 ml/min (C), urea 21.7 (NP) versus 18.5 ml/min (C) and urate 10.5 (NP) versus 8.6 ml/min (C) (P < 0.05 for all). This points to an increased effective peritoneal surface area with nitroprusside. Furthermore, the restriction coefficient for the low molecular weight solutes decreased from 1.28 (C) to 1.23 (NP) (P = 0.02), suggesting some effect also on the size selectivity to these solutes. The effect of nitroprusside on the clearances of serum proteins was more pronounced. The increase with nitroprusside was 34% for beta 2-microglobulin, 70% for albumin, 77% for IgG and 143% for alpha 2-macroglobulin. This reduction in size selectivity was reflected in a decrease in the restriction coefficient for macromolecules from 2.29 (C) to 1.86 (NP), P < 0.01. This implies an increase in the intrinsic permeability of the peritoneal membrane. Kinetic modeling, using computer simulations, was done to analyze these effects in terms of the pore theory, using a convection model and a diffusion model for the transport of macromolecules. Nitroprusside led to an increase of both the large pore radius and the small pore radius and of the unrestricted area over diffusion distance. These effects were more pronounced with the diffusion model. The MTAC CO2 was not different: NP 76.9 and C 84.1 ml/min. MTACs of nitrate were not greater than expected on the basis of the molecular weight during both dwells. The dialysate/plasma (D/P) ratio of cGMP was greater after addition of nitroprusside: 0.36, range 0.21 to 0.77 (C) and 0.74, 0.23 to 2.50 (NP), P = 0.02. With nitroprusside the D/P ratio of cGMP was greater than expected on the basis of its molecular weight (P < 0.001). This points to local generation of cGMP after the addition of nitroprusside, induced by NO. No differences were found in the dialysate concentrations of the prostaglandins (PG) PGE2 and 6-keto-PGF1 alpha and thromboxane B2 after addition of nitroprusside. The transcapillary ultrafiltration rate and the net ultrafiltration rate during four hours were not different with nitroprusside. In conclusion, nitroprusside i.p. increased the effective peritoneal surface area and the intrinsic permeability, but the peritoneal blood flow did not change. The greater than expected D/P ratios of cGMP point to local generation of cGMP with nitroprusside, induced by NO.

Predicting mortality in intensive care patients with acute renal failure treated with dialysis.

Existing prognostic methods were compared in their ability to predict mortality in intensive care unit (ICU) patients on dialysis for acute renal failure (ARF). The clinical goal of this study was to determine whether these models could identify a group of patients where dialysis would provide no benefit because of a near 100% certainty of death even with dialysis treatment. This retrospective cohort study included 238 adult patients who received a first dialysis treatment for ARF in the ICU. This study examined the performance of seven general ICU mortality prediction models and four mortality prediction models developed for patients with ARF. These models were assessed for their ability to discriminate mortality form survival and for their ability to calibrate the observed mortality rate with the expected mortality rate. The observed in hospital mortality was 76% for our patient group. Areas under the receiver operating characteristic curve ranged from 0.50 to 0.78. With the Acute Physiology and Chronic Health Evaluation (APACHE) III and the Liano models, the observed mortality in the highest quintiles of risk were 97% and 98%. In conclusion, although none of the models examined in this study showed excellent discrimination between those patients who died in hospital and those who did not, some models (APACHE III, Liano) were able to identify a group of patients with a near 100% chance of mortality. This indicates that these models may have some use in supporting the decision not to initiate dialysis in a subgroup of patients.

Effect of amino acid based dialysate on peritoneal blood flow and permeability in stable CAPD patients: a potential role for nitric oxide?

Amino acid dialysis solution 1.1% (Nutrineal) contains L-arginine, a substrate for nitric oxide (NO) synthesis. NO causes vasodilation in many organs. To investigate effects of the amino acid dialysis solution on peritoneal permeability and perfusion, standard peritoneal permeability analyses were performed in 10 stable CAPD patients; one with Nutrineal and another with glucose dialysate (Dianeal 1.36%). The mass transfer area coefficient (MTAC) of nitrate and cGMP were calculated to study a possible role of NO. The MTAC of CO2 was measured to estimate peritoneal blood flow. The MTAC of CO2 was higher during the 4-hour dwell with the amino acid solution: median 93 ml/min (amino acid solution) vs. 60 ml/min (glucose solution); p < 0.01. This suggests an increased peritoneal blood flow during the administration of amino acids. Also the MTACs of low molecular weight solutes were greater with amino acids compared to glucose: creatinine 11.6 ml/min vs. 10.0, urea 19.0 vs. 16.6, urate 9.5 vs. 8.0; p < or = 0.01 for all. This points to an increased effective peritoneal surface area during amino acids. The clearances of the macromolecules beta 2-microglobulin and alpha 2-macroglobulin were also greater with the amino acid dialysis solution (p < 0.05), but there was only a small increase in the clearances of albumin and IgG. The increase in albumin loss during the 4-hour dwell with amino acids was only marginal. The MTACs of nitrate and cGMP were similar with the 2 solutions, without evidence of local production of these solutes. No difference was found between the 2 solutions in the dialysate concentrations of the prostaglandins PGE2, 6-keto-PGF1 alpha, PGF2 alpha and TxB2. The transcapillary ultrafiltration rate was higher during the amino acid dwell (p < 0.01), but no significant difference in net ultrafiltration was found, because the lymphatic absorption tended to be slightly greater with amino acids. The difference in transcapillary ultrafiltration with the 2 solutions was probably blood flow dependent, as the peritoneal filtration fraction was essentially the same in the 2 experiments. It is concluded that amino acid dialysis solution had a vasoactive effect. It mainly influenced the peritoneal blood flow and the effective peritoneal surface area. These effects could not be attributed to NO, as judged from nitrate or cGMP MTACs.

Effects of acute and chronic angiotensin converting enzyme inhibition by spirapril on cardiovascular regulation in essential hypertensive patients. Assessment by spectral analysis and haemodynamic measurements.

1. The effects of a first dose and of chronic treatment with spirapril, a novel angiotensin converting enzyme (ACE) inhibitor, on short-term blood pressure and heart rate fluctuations were assessed by fast Fourier spectral analysis. The effects on systemic haemodynamics in supine and standing position were also studied. We treated 11 patients with 3 mg and 13 patients with 12 mg spirapril for 8 weeks. 2. Overall blood pressure variability was not changed by spirapril. By spectral analysis the changes in blood pressure and heart rate variability in various frequency bands can be assessed, which may be related to changes in activity of the autonomic nervous system. The relative power in the mid-frequency band (0.08-0.12 Hz) of supine systolic pressure was 23 +/- 10% during placebo and decreased during treatment with 12 mg to 11 +/- 4% (P < 0.01 vs placebo, first dose) and to 13 +/- 6% (P < 0.01, chronic treatment). Standing systolic mid-frequency power was 38 +/- 12% during placebo and decreased to 27 +/- 9% (P < 0.01 vs placebo) after the first dose of 12 mg, but it did not decrease after chronic treatment (29 +/- 13%). Treatment with 3 mg induced no changes in mid-frequency blood pressure variability. A decrease in power of the mid-frequency band may point to a decrease in sympathetic vascular drive. The power in the high-frequency band (0.15-0.40 Hz) of heart rate did not change after treatment, suggesting that there is no change in the vagal cardiac drive. 3. Supine blood pressure decreased by a decrease in vascular resistance by 16 +/- 23% (3 mg) and 14 +/- 19% (12 mg) after 8 weeks treatment. Heart rate, stroke volume and cardiac output did not change. No orthostatic hypotension occurred after the first dose. In the 12 mg group the orthostatic induced rise in heart rate (compared with supine) increased from + 9 +/- 5 beats min-1 (placebo) to + 14 +/- 4 beats min-1 (P < 0.05) after the first dose. No changes in the orthostatic heart rate increase occurred in the 3 mg group. The orthostatic changes in stroke volume, cardiac output and vascular resistance were not influenced by spirapril. 4. In conclusion, the decrease in mid-frequency blood pressure variability may suggest an inhibitory effect of acute and chronic ACE inhibition upon sympathetic vasomotor control. Vagal activity was not influenced as high-frequency heart rate variability did not change. Acute and chronic ACE inhibition did not blunt important cardiovascular reflexes, as the haemodynamic response to orthostasis remained intact.

Circadian variation of urinary albumin excretion in pregnancy.

OBJECTIVE: The hypothesis was tested that circadian variations in urinary albumin excretion of pregnant women in the third trimester of normal pregnancy are different from nonpregnant individuals. DESIGN: Circadian variability in urinary albumin excretion was studied both in pregnant women and in nonpregnant controls either during normal daily activities or in contrast during continuous bedrest with standardised fluid and food intake to study endogenously generated rhythm. SETTING: Outpatient department and metabolic ward of a university hospital. MAIN OUTCOME MEASURES: Urinary albumin excretion during fixed time periods over the day and the night. RESULTS: Both ambulant pregnant and nonpregnant women have circadian rhythm in urinary albumin excretion but pregnant women have, firstly, a higher 24 h urinary albumin excretion, secondly, smaller relative day-night differences than nonpregnant controls and thirdly, in the metabolic ward some pregnant women demonstrate absence of rhythm. CONCLUSIONS: The higher albumin excretion during pregnancy in 24 h urine collections can largely be explained by a higher excretion during the night, compared with that of nonpregnant women. The day-night difference in urinary albumin excretion of ambulant pregnant women is exogenously determined.

Nitrate in stable CAPD patients and during peritonitis.

During continuous ambulatory peritoneal dialysis (CAPD) peritoneal vessels are dilated. Nitric oxide (NO) causes vasodilation in many organs. Nitrate, a stable metabolite of NO, was measured in plasma and dialysate. In 6 stable CAPD patients standard peritoneal analyses were performed. The mass transfer area coefficient (MTAC) of nitrate was 11.5 mL/min (10.0-17.0 mL/min) (median and range). The MTAC of creatinine was of the same order of magnitude: 10.7 mL/min (8.0-14.2 mL/min), although the molecular weight of nitrate is lower (62 vs 113 dalton). The correlation between the MTAC of nitrate and the MTAC of creatinine indicated diffusion from the circulation and not local production of NO (r = 0.71; p = 0.11). Peritoneal permeability is increased in the acute phase of peritonitis, partly caused by extensive vasodilation. The potential role of NO during peritonitis was investigated in 8 CAPD patients with 11 peritonitis episodes in the acute phase and after recovery. The median dialysate/plasma (D/P) ratio of nitrate in the acute phase was 1.47 (range 0.96-2.55), which was higher than after recovery: 1.07 (0.99-1.75), p < 0.05. No relation was found between the D/P ratio of nitrate and the D/P ratio of TNF alpha (tumor necrosis factor). In conclusion, dialysate nitrate levels in stable CAPD patients are likely to be determined by diffusion from the circulation. D/P ratios exceeding 1.0 during the acute phase of peritonitis are probably the result of local NO production. This may contribute to the marked vasodilation during peritonitis.