Dialysis in neonates with inborn errors of metabolism.

BACKGROUND: Certain inborn errors of metabolism become manifest during the neonatal period by acute accumulation of neurotoxic metabolites leading to coma and death or irreversible neurological damage. Outcome critically depends on the immediate elimination of the accumulated neurotoxins. Recent technological progress provides improved tools to optimize the efficacy of neonatal dialysis. METHODS: We report our experience with continuous venovenous haemodialysis (CVVHD) in six neonates with hyperammonaemic coma due to urea-cycle disorders or propionic acidaemia and in one child with leucine accumulation due to maple-syrup urine disease (MSUD), in comparison with five patients managed by peritoneal dialysis (PD) (2 hyperammonaemia, 3 MSUD). Application of a new extracorporeal device specifically designed for use in small children permitted the establishment of stable blood circuits utilizing small-sized catheters, and the tight control of balanced dialysate flows over wide flow ranges. RESULTS: Plasma ammonia or leucine levels were reduced by 50% within 7.1 +/- 4.1 h by CVVHD and within 17.9 +/- 12.4 h by PD (P<0.05). Also, total dialysis time was shorter with CVVHD (25 +/- 21 h) than with PD (73 +/- 35 h, P<0.02). A comparison of the CVVHD results with published literature confirmed superior metabolite removal compared to PD, and suggested comparable efficacy as achieved with continuous haemofiltration techniques. Apart from accidental pericardial tamponade during catheter insertion in one case, no major complications were noted with CVVHD. In three of the five PD patients, dialysis was compromised by mechanical complications. None of the MSUD patients but four children with urea-cycle disorders died, two during the acute period and two later during the first year of life, with signs of severe mental delay. Of the eight children presenting with hyperammonaemic coma, the four with the most rapid dialytic ammonia removal rate (50% reduction in < 7 h) survived with no or moderate mental retardation, whereas slower toxin removal was always associated with a lethal outcome. Simulation studies showed that the efficacy of neonatal CVVHD is limited mainly by blood-flow restrictions. CONCLUSIONS: While CVVHD is the potentially most efficacious dialytic technique for treating acute metabolic crises in neonates, utmost care must be taken to provide an adequately sized vascular access.     

Efficacy and safety of intermittent hemodialysis in infants and young children with inborn errors of metabolism

Background

Intermittent hemodialysis (IHD) is the most efficient form of renal replacement therapy (RRT) for removing toxic substances from patients’ bodies. However, the efficacy and safety of IHD in infants and young children with inborn errors of metabolism are still not clear.

Methods

This retrospective study included patients with urea cycle disorders, maple syrup urine disease, and methylmalonic acidemia who received IHD or non-IHD RRT at our hospital between 2001 and 2012 to remove ammonia, leucine, or methylmalonic acid. Both the efficacy and safety of the RRT were evaluated.

Results

Thirty-five courses of RRT, including 25 courses of IHD and ten courses of non-IHD RRT, for 15 patients were included in the analysis. Before 2006, non-IHD RRT procedures, including peritoneal dialysis (PD) and continuous venous-venous hemofiltration (CVVH), were the most often used; from 2006 onwards IHD was used. There was one procedure-unrelated death. Catheter penetration occurred in one course of IHD. The efficacy data revealed that both the median duration of dialysis and the median 50 % toxin reduction time were shorter in IHD than in non-IHD RRT.

Conclusions

In infants and young children with inborn errors of metabolism, IHD is safe and more efficient than non-IHD RRT at removing toxins.     

Utility of hemodialysis in maple syrup urine disease

Maple syrup urine disease (MSUD) is an inborn error of metabolism stemming from a deficiency in 2-ketoacid dehydrogenase and resulting in the systemic accumulation of branched chain amino acids (BCAAs). Affected children may suffer profound developmental and cognitive impairment from exposure to high levels of BCAA and their associated neurotoxic metabolites. Endogenous renal clearance of BCAA is limited and several therapeutic modalities including intensive nutritional regimens, exchange transfusions, peritoneal dialysis, and continuous hemofiltration have been utilized in neonates with MSUD, all of which have had varying success in reducing systemic BCAA levels. In this report, a symptomatic 7-day-old 3-kg neonate with MSUD underwent treatment with a combination of early hemodialysis and aggressive enteral feedings of a metabolically appropriate formula. This approach results in a 75% reduction of systemic toxin levels within 3 h. When compared to other reported modalities of therapy for symptomatic neonates with MSUD, this approach appears to be most efficacious. Moreover, by minimizing the amount of time that an affected neonate is exposed to neurotoxic levels of BCAAs, long-term developmental and cognitive capabilities may be preserved. Received: 7 April 2000 / Revised: 15 November 2001 / Accepted: 17 November 2001     

Renal dysfunction in methylmalonic acidurias: review for the pediatric nephrologist

Methylmalonic acidurias are a heterogeneous group of inborn errors of branched-chain amino acid metabolism. Depending on the underlying etiology, acute or chronic renal disease constitutes major (long-term) complications. In recent decades, overall survival has improved due to optimized treatment strategies based on the use of standardized emergency protocols and dialysis techniques. The majority of these patients, especially those having mut°, cblB, and cblA deficiency, are at increased risk of developing chronic kidney disease secondary to tubulointerstitial nephritis to require hemo- or peritoneal dialysis. Kidney and/or liver transplantation, as organ replacement, or even gene therapy on a limited scale, are controversially discussed treatment options in methylmalonic acidurias. The pathophysiological basis of renal disease has not been clarified in detail until now, but a severe mitochondrial dysfunction and an impairment of tubular dicarboxylic acid transport due to accumulated toxic metabolic compounds has been recently proposed. Another severe renal complication of methylmalonic acidurias is the occurrence of cblC-associated infantile atypical hemolytic syndrome, which can result in acute kidney injury. Close collaboration between (pediatric) nephrologists and metabolic specialists is required for the long-term management of these patients.     

Peritoneal dialysis in neonates with inborn errors of metabolism: is it really out of date?

Peritoneal and extracorporeal dialysis are used to treat newborns affected by inborn errors of metabolism to minimize the effects of the acute accumulation of neurotoxic metabolites that can produce irreversible and severe neurological damage and even death. In recent papers, extracorporeal dialysis has been described as more effective than peritoneal dialysis in improving the prognosis in newborns with inborn errors of metabolism and hyperammonemia. However, it appears that the outcome is primarily related to the duration of neonatal hyperammonemic coma. Here we report seven newborns with hyperammonemia caused by inborn errors of metabolism (five with organic acidemias, two with urea-cycle disorders). They received dietetic and pharmacological treatment as well as peritoneal dialysis. Four of the five patients with organic acidemia survived with and without mild neurological impairment (follow-up 3.5–10 years). One died from bacterial sepsis after peritoneal dialysis was discontinued and the peritoneal catheter was removed. One of the two patients affected by urea-cycle disorders, a boy, died during the neonatal period, and the other, a girl, died at the age of 13 months due to severe neurological damage. Our results demonstrate that peritoneal dialysis may still be an effective treatment for neonatal hyperammonemia caused by inborn errors of metabolism. Furthermore, peritoneal dialysis can be administered quickly and easily in all settings, clearly an advantage when fast intervention is so crucial.     

Treatment dose and the elimination rates of electrolytes,vitamins, and trace elements during continuous veno-venous hemodialysis (CVVHD)

Introduction

During continuous renal replacement therapy, achievement of recommended treatment dose is important. However, relevant substrate loss may occur and recommended nutrition during critical illness could not be sufficient for higher dialysis doses. We investigated the correlation of dialysis dose and substrate loss for a broad range of dialysis doses.

Methods

Forty critically ill patients with acute kidney injury undergoing citrate CVVHD were included in this prospective study. Three different corresponding blood flow (BF) and dialysate flow (DF) rates were applied (BF/DF: 100 ml/min, 2000 ml/h; 80 ml/min, 1500 ml/h; 120 ml/min, 2500 ml/h). Delivered effluent flow rate (DEFR) was calculated and correlated with losses of vitamins, electrolytes, and trace elements during recommended nutritional supplementation.

Results

For folic acid, vitamin B12, zinc, inorganic phosphate, and magnesium, no correlation of losses and DEFR was detected. For ionized calcium, a correlation was observed and additional substitution was required.

Conclusion

Clinically relevant loss of folic acid, vitamin B12, zinc, inorganic phosphate, and magnesium was not observed for differently used dialysis doses of CVVHD, and the loss was covered sufficiently by daily recommended nutritional supplementation. Increased loss of ionized calcium for higher dialysis doses occurred during citrate CVVHD. Therefore, a strict protocol must maintain calcium homeostasis to avoid calcium depletion.

     

Sustained low-efficiency dialysis versus continuous veno-venous hemofiltration for postsurgical acute renal failure

Background

In postsurgical acute renal failure patients with moderate unstable hemodynamics or fluid overload, the choice of dialysis modality is difficult. This study was performed to compare the outcomes between the sustained low-efficiency dialysis (SLED) and continuous veno-venous hemofiltration (CVVH) in these patients.

Methods

Sequential postsurgical acute renal failure patients undergoing acute dialysis with CVVH (2002-2003), or SLED (2004-2005) as a result of severe fluid overload or moderately unstable hemodynamics were analyzed. Multivariate analyses of comorbidity, disease severity before initiating dialysis, biochemical measurements, and hemodynamic parameters for 3 days after the first dialysis session were performed by fitting multiple logistic regression models to predict patient's 30-day after hospital discharge (AHD) mortality.

Results

Among the 101 recruited patients, 38 received SLED and the rest received CVVH. The 30-day AHD mortality was 62.4%. The independent risk factors of 30-day AHD mortality included older age (P = .008), lower first postdialysis mean arterial pressure (MAP) (P = .021), higher first postdialysis blood urea nitrogen level (P = .009), and absence of a history of hypertension (P = .002). A further linear regression analysis found that dialysis using SLED was associated with higher first postdialysis MAP (P = .003).

Conclusions

Among the postsurgical patients requiring acute dialysis with severe fluid overload or moderately unstable hemodynamics, the patients treated with SLED had a higher first postdialysis MAP than those treated with CVVH, which led to lower mortality. Further multicenter randomized clinical trials of larger sample size are needed to compare the effects of SLED and CVVH on the outcomes of postsurgical acute dialysis patients.     

Biotinidase deficiency: New directions and practical concerns

Opinion statement Biotinidase deficiency is a readily treatable inherited disorder. Discovery of the enzyme deficiency as the cause for late-onset multiple carboxylase deficiency initially seemed to answer almost all of the questions about the disorder. However, as is the case for most inborn errors of metabolism, finding the enzyme that causes the disorder, cloning the gene, and determining the spectrum of clinical features of the disease only opens a Pandora’s box. As researchers have found, there are still many important and interesting questions about this disorder that must be addressed and answered. However, when compared with other inherited metabolic diseases, biotinidase deficiency is still one of the most readily treatable. If a child must have an inborn error of metabolism, let it be biotinidase deficiency and let it be identified by newborn screening.     

CVVHD treatment with CARPEDIEM: small solute clearance at different blood and dialysate flows with three different surface area filter configurations

Background

The CARdiorenal PEDIatric EMergency (CARPEDIEM) machine was originally designed to perform only continuous venovenous hemofiltration (CVVH) in neonatal and pediatric patients. In some cases, adequate convective clearance may not be reached because of a limited blood flow. In such conditions, the application of diffusive clearance [continuous venovenous hemodialysis (CVVHD)] would help optimize blood purification. In this study, the CARPEDIEM? machine was modified to enable the circulation of dialysis through the filter allowing testing of the performance of CARPEDIEM? machine in CVVHD.

Methods

Three different polyethersulfone hemodialyzers (surface area?=?0.1 m², 0.2 m², and 0.35 m², respectively) were tested in vitro with a scheduled combination of plasma flow rates (Qp?=?10-20-30 ml/min) and dialysis fluid flow rate (Qd?=?5-10-15 ml/min). Three sessions were performed in co-current and one in counter-current configuration (as control) for each filter size. Clearance was measured from the blood and dialysate sides and results with mass balance error greater than 5 % were discarded.

Results

Urea and creatinine clearances for each plasma/dialysate combination are reported: clearance increase progressively for every filter proportionally to plasma flow rates. Similarly, clearances increase progressively with dialysate flow rates at a given plasma flow. The clearance curve tends to present a steep increase for small increases in plasma flow in the range below 10 ml/min, while the curve tends to plateau for values averaging 30 ml/min. As expected, the plateau is reached earlier with the smaller filter showing the effect of membrane surface-area limitation. At every plasma flow, the effect of dialysate flow increase is evident and well defined, showing that saturation of effluent was not achieved completely in any of the experimental conditions explored. No differences (p?>?0.05 for all values) were obtained in experiments using whole blood instead of plasma or using co-current versus counter-current dialysate flow configuration.

Conclusions

Although plasma flow and filter surface give an important contribution to the level of clearance urea and creatinine, it appears evident that dialysate flow plays an essential role in the blood purification process, justifying the use of CVVHD versus CVVH in case of high dialysis dose requirement and/or limited blood flow rate.

     

Successful management of extreme hypernatraemia by haemofiltration in a patient with severe metabolic acidosis and renal failure.

Sir, Extreme hypernatraemia is rare in adults. Due to the fact thatrapid correction of hypernatraemia may result in neurologicalcomplications, a gradual reduction of sodium concentration isgenerally advised. However, it is difficult in patients withextreme hypernatraemia, severe metabolic acidosis and renalfailure. We describe a patient with extreme hypernatraemia (serumNa⁺ 202 mEq/l), severe metabolic acidosis ( 7.6 mEq/l) and renal failure who was successfully treated withcontinuous venovenous haemofiltration (CVVH) with a portionof commercial CVVH replacement fluid and additional sodium bicarbonate.We believe this is the first case report of such a novel treatmentand may     

Perioperative management of a child with very-long-chain acyl-coenzyme A dehydrogenase deficiency

Very-long-chain acyl-coenzyme A dehydrogenase deficiency is an inborn error of fatty acid metabolism. The clinical presentation of this disease in children is either a severe form with onset of symptoms in the first months of life, cardiomyopathy, metabolic acidosis, myopathy and a high mortality, or a less severe form manifesting mainly with hypoglycaemia. Perioperative fasting and (even emotional) stress can trigger metabolic decompensation through the altered metabolism of endogenous fatty acids resulting in hypoglycaemia, acute cardiac and hepatic dysfunction and rhabdomyolysis. We report the perioperative management of a 9-year-old boy suffering from the severe form of this disease who underwent circumcision. Metabolism was kept stable in this child by using a glucose--electrolyte infusion throughout the perioperative period to avoid the biochemical consequences of fasting and a benzodiazepine--opioid technique combined with regional anaesthesia to minimize the stress response. Considering reports about a possible interference of propofol with fatty acid oxidation and to avoid the unnecessary administration of fatty acids, propofol should not be used in these patients.     

A biphasic dialytic strategy for the treatment of neonatal hyperammonemia

Background

Neonates with inborn errors of metabolism (IEM) often develop hyperammonemia which, if not corrected quickly, may result in poor neurologic outcomes. As pharmacologic therapy cannot rapidly lower ammonia levels, dialysis is frequently required. Both hemodialysis (HD) and standard-dose continuous renal replacement therapy (CRRT) are effective; however, HD may be followed by post-dialytic ammonia rebound, and standard-dose CRRT may not effect a rapid enough decrease in ammonia levels.

Case-Diagnosis/Treatment

We present two cases of IEM-associated neonatal hyperammonemia in which we employed a biphasic, high-dose CRRT treatment strategy, initially using dialysate flow rates of 5,000 mL/h (approximately 40,000 mL/h/1.73 m²) in order to rapidly decrease ammonia levels, then decreasing the dialysate flow rates to 500 mL/h (approximately 4,000 mL/h/1.73 m²) in order to prevent ammonia rebound.

Conclusions

This biphasic dialytic treatment strategy for neonatal hyperammonemia effected rapid ammonia reduction without rebound and accomplished during a single dialysis run without equipment changes.     

We use Continuous Renal Replacement Therapy for Overdoses and Intoxications

Extracorporeal modalities for the removal of drugs and toxins are indicated for the treatment of overdoses and intoxications. Well‐established modalities include hemodialysis (HD), high‐flux HD (HfD), and charcoal hemoperfusion (HP). Recently, there have been increasing reports on the use of continuous renal replacement therapy (CRRT), such as continuous veno‐venous hemodialysis (CVVHD), continuous veno‐venous hemofiltration (CVVH) or CVVH combined with dialysis (CVVHDF). In the present article, we will discuss the various factors that determine the clearance of drugs and toxins and accordingly, we will propose that with few exceptions, CRRT does not have a role in the routine management of intoxications.     

Cerebrovascular autoregulation in critically ill patients during continuous hemodialysis

Purpose

In chronic renal failure, intermittent hemodialysis decreases cerebral blood flow velocity (CBFV); however, in critically ill patients with acute renal failure, the effect of continuous venovenous hemodialysis (CVVHD) on CBFV and cerebrovascular autoregulation (AR) is unknown. Therefore, a study was undertaken to investigate the potential effect of CVVHD on CBFV and AR in patients with acute renal failure.

Methods

This cohort study investigated 20 patients with acute renal failure who required CVVHD. In these patients, the CBFV and index of AR (Mx) were measured using transcranial Doppler before and during CVVHD.

Results

The median Mx values at baseline were 0.33 [interquartile range (IQR): 0.02-0.55], and during CVVHD, they were 0.20 [0.07-0.40]. The differences in Mx (CVVHD – baseline) was (median [IQR]) ?0.015 [?0.19-0.05], 95% confidence interval (CI) ?0.16 to 0.05. The Mx was > 0.3 in 11/20 patients at baseline measurement. Six of these patients recovered to Mx < 0.3 during CVVHD. The CBFV was (median [IQR]) 47 [36-59] cm·sec^?1 at baseline and 49 [36-66] cm·sec^?1 during CVVHD. The difference of CBFV was 0.0 [?4 - 2.7], 95% CI ?2.5 to 4.2.

Conclusion

Compared with patients with intermittent hemodialysis, CVVHD did not influence CBFV and AR in critically ill patients with acute renal failure, possibly due to lower extracorporeal blood flow, slower change of plasma osmolarity, and a lower fluid extraction rate. In a subgroup of patients with sepsis, the AR was impaired at baseline in more than half of the patients, and this was reversed during CVVHD. The trial was registered at ClinicalTrials.gov ID: NCT01376531.     

Continuous arteriovenous hemodiafiltration in the acute treatment of hyperammonaemia due to ornithine transcarbamylase deficiency

BACKGROUND: Acute hyperammonemia caused by urea cycle disorder is a medical emergency for which immediate managements should be taken to minimize permanent brain damage. Among different enzyme defects, ornithine transcarbamylase deficiency (OTC) is one of the most common enzyme defect in urea cycle disorders. We utilized continuous renal replacement therapy techniques in the acute treatment of hyperammonemia due to ornithine transcarbamylase deficiency. PATIENTS AND METHODS: Three male neonates with elevated serum ammonia levels were shown, based on urine organic acid analysis and serum amino acid studies, to have OTC deficiency. Administration of sodium benzoate and sodium phenylacetate for activating alternative nitrogen waste pathway were used associated with protein restriction. Other modalities, including blood exchange transfusion, peritoneal dialysis, continuous renal replacement therapy were utilized in an attempt to lower serum ammonia concentration. RESULTS: We report the successful use of continuous arteriovenous hemofiltration (CAVH), continuous arteriovenous hemodialysis (CAVHD), continuous arteriovenous hemodiafiltration (CAVHDF) in the acute management of hyperammonemia due to OTC deficiency. We also compared the ammonia clearance between peritoneal dialysis, exchange transfusion, CAVH, CAVHD and CAVHDF. It demonstrated the evidence that CAVHDF provides the best ammonia clearance. CONCLUSION: Continuous renal replacement therapy including CAVH, CAVHD, and CAVHDF may be the alternative techniques for acute management of hyperammonemia in inborn error of metabolism when dialysis machine is not available. Our data suggests CAVHDF provides the best ammonia clearance.     

Anesthetic management of a patient with 3-methylcrotonyl-CoA carboxylase deficiency

Patients with inborn errors of metabolism require special considerations in perioperative care. In the following case report, we describe the successful management of a patient with 3-methylcrotonyl-CoA carboxylase deficiency, a deficit that causes a secondary carnitine deficiency and impaired beta oxidation. Patients may have significant underlying cardiomyopathy, and are at risk for metabolic decompensation, acidosis, and hypoglycemia during periods of stress.     

Determinants of vancomycin clearance by continuous venovenous hemofiltration and continuous venovenous hemodialysis

The clearance of vancomycin is significantly reduced in patients with acute, as well as, chronic renal failure. Although multiple-dosage regimen adjustment techniques have been proposed for these patients, there is little quantitative data to guide the individualization of vancomycin therapy in acute renal failure patients who are receiving continuous renal replacement therapy (CRRT). To determine appropriate vancomycin dosing strategies for patients receiving continuous venovenous hemofiltration (CVVH) and continuous venovenous hemodialysis (CVVHD), we performed controlled clearance studies in five stable hemodialysis patients with three hemofilters: an acrylonitrile copolymer 0.6 m2 (AN69), polymethylmethacrylate 2.1 m2 (PMMA), and polysulfone 0.65 m2 (PS). Patients received 500 mg of vancomycin intravenously at least 12 hours before the start of the clearance study. The concentration of vancomycin in multiple plasma and dialysate/ultrafiltrate samples was determined by EMIT (Syva, Palo Alto, CA). The diffusional clearance and sieving coefficient (SC) of vancomycin were compared by a mixed-model repeated-measures analysis of variance (ANOVA) with filter and blood (Q(B)), dialysate inflow (Q(DI)), or ultrafiltration rate (Q(UF)) as the main effects and patient as a random effect. Vancomycin was moderately protein bound in these patients; free fraction ranged from 49% to 83%. The SCs of the three filters were similar and significantly correlated with the free fraction of vancomycin (P = 0.01; r2 = 0.465). Significant linear relationships were observed between the diffusional clearance of vancomycin and Q(DI) for all three filters: AN69 (slope = 0.482; r2 = 0.880); PMMA (slope = 0.853; r2 = 0.966); and PS (slope = 0.658; r2 = 0.887). The slope of this relationship for the PMMA filter was significantly greater than that of the AN69 and PS filters. The clearance of vancomycin, urea, and creatinine, however, was essentially constant at all Q(B)s for all three filters. Thus, the clearance of vancomycin was not membrane dependent during CVVH. However, during CVVHD, membrane dependence of vancomycin clearance was noted at a Q(DI) greater than 16.7 mL/min; vancomycin clearance with PMMA at a Q(DI) of 25 mL/min was 66% and 43% greater than that with the AN69 and PS filters, respectively. CVVH (62% to 262%) and CVVHD (90% to 540%) can significantly augment the clearance of vancomycin in acute renal failure patients. Dosing strategies for individualization of vancomycin therapy in patients receiving CVVH and CVVHD are proposed.