The importance of prevention of catabolism by administering high kcal feedings enterally or parenterally has been supported by 5 clinical studies, 2 literature reviews, and 3 expert opinions (F.57, F.596, F.514, F.520, F.2810, F.3399, F.3109, G.17, G.51, G.79). Provision of 110 – 150 kcal/kg body weight/day or 1.1 to 1.5 times energy requirements using IV 10% dextrose at 8 – 12 mg glucose /kg body weight/minute, or age-dependent glucose requirements to maintain blood glucose at 120-170 mg/dL, were recommended (F.2810, F.3399, F.3109) and use of IV lipids to increase energy intake (F.2810, G.51).

Delphi 1:

There was consensus (82% of all respondents agreed) that meeting the age-appropriate DRI for energy should be appropriate for individuals with PROP.

Comments: included that some may need more, some less and energy intake should be based on growth and weight change.to in energy intake should meet estimated needs to decrease catabolism.

There was consensus (100% of respondents agreed) that energy intake should at least meet estimated needs to decrease catabolism

There was not consensus (100% of the MD and only 50% of the RD respondents agreed) about the use of 20% IV lipids at 2 mg/kg body weight/day to assist with meeting energy needs at first presentation or during acute illness

Insulin has been reported to promote anabolism by increasing tolerance to increased glucose infusions based on clinical case reports, literature reviews and clinical experience reports of individuals with PROP (F.2738, F.2859, F.520, F.3109, F.58, F.2810, F.2738, G.17, G.79). The recommended insulin delivery was at 0.05-0.2 IU/kg/hour (F.502) and at 0.2 – 0.3 IU/kg/hour with high glucose infusions to treat hyperglycemia (F.520, F.2810).

Delphi 1:

There was consensus (82% of all respondents agreed) with the use of insulin to allow sufficient glucose infusion for anabolism and to prevent hyperglycemia.

Gradual rehydration over the first 48 hours of initial acute presentation with fluids at 150 – 180 ml/kg body weight/24 hours or up to 1.5 times maintenance, with appropriate electrolytes and avoidance of Ringers lactate solution, has been reported in two clinical studies (F.57, F.502), recommendations from expert committees (F.3273, F.3399), literature reviews (F.439, F.2810) and clinical experience (G.51, G.78, G.79). Avoidance of hypotonic fluids and over-aggressive rehydration has been shown to decrease risk of cerebral edema (F.57, F.3399, F.2810). High volume fluids along with adequate urine output promoted urinary excretion of toxic metabolites (F.2810, G.18, G.19). Caution with underestimating intracellular dehydration as adequate rehydration was essential to optimize outcomes (F.57, F.3399, F.502).

Delphi 1:

There was consensus (100% of respondents agreed) that IV fluids with 10% dextrose provided at 1.5 – 2 times maintenance should be used during acute illness

See Question #3 for evidence and recommendations on the use of carnitine in individuals with PROP.

Use of hemofiltration has been described in case reports /series, literature reviews and clinical practice reports for exogenous ammonia and propionate toxin removal upon acute presentation (F.582, F.484, F.526, F.2738, F.596, F.3384, F.3109, F.3252, F.450, F.2810, F.514, G.17, G.20, G.64, G.79). In a 10 year retrospective review (F.3252) of 14 neonates with 5 having PROP; 85% of the patients achieved ammonia <200 µmol/l in 24 hours or less, hypotension needing intervention occurred in 7 (50%) patients, and 64% survived (80% of PROP patients), although no relationship between time needed to lower ammonia and survival was found. Use of hemodialysis or extracorporeal membrane oxygenation (ECMO) has been used with individuals presenting with hyperammonemia (>300 µmol/L), severe acidosis/electrolyte imbalance, and with compromised neurologic status, coma or failure to improve and/or increase respiratory rate (F.3252). Continuous hemofiltration was reported as the preferred method over peritoneal dialysis as it allowed administration of larger volumes of fluids from TPN without risk of over-hydration, and it was the most effective and rapid method of removing small solutes such as ammonia (F.241, F.582, F.3399).

There were no statements in the Delphi surveys that addressed outcomes for individuals with PROP who have undergone hemoflitration.

In literature reviews, case series, and clinical experiences, it has been reported that total protein was removed upon acute presentation, (F.520, F.3273, F.502, F.3109, F.3399, G.19, G.78) and reintroduced as early as possible, preferably within 24 to 48 hours after discontinuation and sooner if decompensation was determined to be due to protein deficiency. Over-restriction of protein should be avoided due to the risk of growth failure, as reported in a literature review (F.439), where ~40% of the patients demonstrated decreased growth, 30% had immune suppression, and 10% had bone fractures due to their poor diets.

Delphi 2:

There was greater consensus among the RD respondents vs.MD respondents pertaining to the duration of protein restriction:

There was not consensus (83% of RD and only 57% of MD agreed, for a total of 77% agreement) that protein should be restricted for no more than 12 - 48 hours.

85% of all respondents agreed that protein restriction should not be for longer than 48 hours

92% of all respondents agreed that protein may be reintroduced via either enteral or parenteral feedings.

Practice recommendations suggested that complete protein should be introduced at 0.5 - 0.75 gm/kg/day   (G.18, G.19, G.78, G.79). In 30 PROP patients in acute metabolic crisis (F.502, F.3273), early administration of complete protein at 0.5 – 0.7 g/kg body weight/day with careful introduction of non-propiogenic amino acids achieved a positive nitrogen balance.

Delphi 2:

There was not consensus among the respondents regarding the amount of protein to be used when initiating introduction or re-introduction after restriction.

75% of RD and 71% of MD respondents agreed that, when introducing enteral or parenteral protein, to start with 0.5 to 0.75 gm/kg/d.

There was very little agreement to start with amounts of 0.25 - 0.5 gm/kg/day (only 8% of group agreeing to this amount) or >0.75 gm/kg/day of protein (19% of group agreeing to this amount). .

Based on literature reviews and practice guidelines, protein intake has been recommended to be advanced with complete protein by 0.25 - 0.5 gm/kg/day as tolerated. Literature reviews and practice guidelines have reported that amino acids added to meet minimal daily requirements, though specific amounts varied widely between patients and were determined based on disease severity, age, and growth rate, and titrated according to biochemical monitoring, with even distribution of amino acids over the day (F.520, F.526, G.19, G.79). 

Delphi 2:

There was not consensus among the respondents on how to advance enteral or parenteral protein during acute illness:

42% of all respondents agreed that the increase should be by 0.25gm/kg/day using both propiogenic-free and propiogenic-containing protein sources.

48% of all respondents agreed that the increase should be by 0.25gm/kg/day using only propiogenic-containing protein sources..

Provision of energy using IV 10% dextrose at 8 – 12 mg/kg/minute, or age-dependent glucose requirements to maintain blood glucose at 120-170 mg/dL, were reported (F.2810, F.3399, F.3109) and weight gain was achieved as reported in one case series on this regimen (F.514). Based on case reports, literature review, and clinical experience, an amino acid- free parenteral solution has been started for the first 24-48 hours, to provide energy via dextrose and lipids (F.596, F.520, F.2811, G.79). Use of parenteral nutrition support during acute crises minimized catabolism and improved recovery (F.520, F.58, F.3399, F.439, G.18, G.20, G.78, G.79) though specifics in outcomes were not provided. Placement of a central catheter has been used for provision of both hydration and energy (F.582, F.3273, G.79).

Delphi 1:

There was consensus (100% of all respondents agreed) with the use of IV fluids with 10% dextrose provided at 1 1/2 to 2 times maintenance during acute management.

The addition of 20% IV lipids have been added at 2 gm/kg/day to increase energy intake (F.2810, G.51).

Delphi 1:

There was not consensus (50% of RD and 100% the MD respondents agreed) with the use of 20% intralipids at 2gm/kg/day during acute management.

Use of a standard IV amino acid solution (Travosol, Aminosyn and Trophamine) has been reported (F.253, F.2738) with essential and nonessential amino acids added at amounts recommended in Topic 2.2.2 and advanced per 2.2.3. Although the TPN complete protein solutions have propiogenic amino acids, they were reported to be used safely by avoiding excessive amounts of protein and titrating based on biochemical monitoring (F.252, F.3399, G.79).

Delphi 2:

There was consensus (92% of all respondents agreed) that protein may be re-introduced via parenteral feeding.

A propiogenic-free amino acid TPN solution can be used when the protein DRI cannot be tolerated from the standard IV amino acid solution during times when prolonged bowel rest is needed. A parenteral mixture of amino acids with no or reduced concentrations of the propiogenic amino acids were recommended to be used in individuals with intestinal abnormalities (G.17), though no data regarding impact on outcomes were reported.

Delphi 2:

There was consensus (84% of all respondents agreed) that when using TPN during prolonged bowel rest, supplementation with propiogenic amino acid-free TPN can be used when the total protein recommendation cannot be met using standard TPN. 

Evidence

Use of propiogenic-free amino acid medical foods are recommended when the protein DRI cannot be tolerated from a complete protein source. In literature reviews, reports on clinical experience, and case reports/series, a diet restricted in the offending amino acids ILE, VAL, MET and THR based on individual tolerance and growth and supplemented with propiogenic-free amino acid medical food to meet the RDA for total protein, were reported to result in more favorable outcomes as well as to provide a good source of vitamins and minerals missing in a low protein diet (F.1387, F.3387, F.3399, F.242, F.502, G.18, G.51, G.67, G.80). In two reports, inadequate growth, developmental delay, movement disorders, and marginal outcomes were reported in patients who did not receive medical foods (F.437, F.484). 

Consensus based on clinical practice

Delphi 2:

There was consensus (100% of the MD and RD respondents agreed)  that when the DRI cannot be met using standard formula or intact protein, propiogenic amino acid-free medical food should be added to the enteral feedings.

Use of tube feedings have been shown to be effective to reduce the number of hospitalizations and have led to improved outcomes when used to supplement oral nutrient intake, administer medications, reduce the number of hours fasting via overnight feedings or more frequent daytime feedings, and provide nutritional support during periods of anorexia and vomiting associated with compromised metabolic control based on reports from literature reviews and a report on clinical experience and 4 case series publications (F.3109, F.3273, F.3403, F.3399, F.242, F.249, F.502, F.3318, G.80). Five case reports/series and a review of the literature reported frequent feeding difficulties the first 2 – 5 years of life due to muscular hypotonia with swallowing difficulties and developmental delay, frequent episodes of metabolic decompensation, frequent illnesses, and compromised GI tolerance (F.253, F.56, F.534, F.248, F.251, F.242, G.51) and can lead to protein deficiency as demonstrated by hypoalbuminemia, pitting edema, and erythematous scaly patches on the skin.

Enteral tube feedings can be used to provide nutritional support when there is anorexia due to poor metabolic control. Based on two case reports, literature reviews, and reports on clinical experience, nasogastric or gastrostomy tubes have been successfully used and recommended because of failure to thrive, anorexia, and dysphagia or if patients are neurologically compromised (F.439, F.3273, F.2807, G.18, G.19, G.78). In one of these reports (F.2807), 49% required percutaneous gastrostomy feedings by the age of 2 yr with 15% exclusively tube fed.

Delphi 1:

There was consensus among all respondents that enteral feedings should be started as soon as possible when tolerated.  The question did not define enteral feedings as oral or G tube.

There was support by all attendees at the nominal group meeting for this recommendation

Use of propiogenic-free amino acid medical foods are recommended when the protein DRI cannot be tolerated from a complete protein source. In literature reviews, reports on clinical experience, and case reports/series, a diet restricted in the offending amino acids ILE, VAL, MET and THR based on individual tolerance and growth and supplemented with propiogenic-free amino acid medical food to meet the RDA for total protein, were reported to result in more favorable outcomes as well as to provide a good source of vitamins and minerals missing in a low protein diet (F.1387, F.3387, F.3399, F.242, F.502, G.18, G.51, G.67, G.80). In two reports, inadequate growth, developmental delay, movement disorders, and marginal outcomes were reported in patients who did not receive medical foods (F.437, F.484). 

Delphi 2:

There was consensus (100% of the MD and RD respondents agreed)  that when the DRI cannot be met using standard formula or intact protein, propiogenic amino acid-free medical food should be added to the enteral feedings.

Tube feedings can be used to reduce the number of hours fasting via overnight feeding or more frequent daytime feedings. When routine overnight feedings were implemented, regardless of patient’s appetite, two-thirds of the patients survived and with a decreased number of hospitalizations to treat metabolic decompensation (F.56). Growth and body composition were reported to be near normal in most, though unsatisfactory in a few (F.56).

It has been recommended that extended fasting periods not exceed 4 – 6 hours for infants (<=12 months of age) or 8 hours for children (>12 months of age) and adolescents. Based on literature reviews and reported clinical experience, most individuals have required overnight feedings to prevent long intervals of fasting. The importance of avoidance of fasting and benefits of frequent feedings, have been reported in the literature and clinical practice, suggesting infants should be fed every 4 hours (F.597, G.20, G.67). Based on two case series, and practice literature, avoidance of more than 8 hours fasting after infancy has been reported to decrease/prevent metabolic decompensation  (F.439, F.437, F.3109, F.526, G.17, G.18, G.19, G.20, G.51, G.80). An increase in propionate metabolites was reported in individuals during fasting (F.507), though no specific outcomes on the reduction of metabolic decompensation were provided.

Delphi 1:

There was consensus (82% of all respondents agreed) that medical foods should be prescribed to be consumed at least 3 times a day.

Comments: 2 respondents stated that some patients require tube feedings at night.

Delphi 2:

There was not consensus (although fairly high agreement - 77% of all respondents) regarding the duration of fasting periods stated as: infants not exceeding 4 - 6 hours of fasting and children (>12 months of age) not exceeding 8 hours.

Several case reports/series and a review of the literature reported frequent feeding difficulties the first 2 – 5 years of life due to muscular hypotonia with swallowing difficulties and developmental delay, frequent episodes of metabolic decompensation, frequent illnesses, and compromised GI tolerance (F.253, F.56, F.534, F.248, F.251, F.242, G.51). Use of adaptive and assistive feeding devises has been recommended to compensate for these deficits and assist with promoting oral intake (F.511). Referral to feeding or speech therapy may be needed in certain circumstances (F.438).

There were no statements in the Delphi surveys that addressed the use of adaptive feeding devices for individuals with PROP.

Practice guidelines advocate for provision of extra attention and encouragement for promoting oral intake. Introduction of solid foods was reported to be slow due to refusal of infants to accept a variety of solid foods (F.3399).  They recommended a longer time be allowed for finger feedings (up to 5 years of age) and to provide extra attention and encouragement of oral feedings. This approach worked well in those without neurological handicaps (F.251).   

All attendees in the nominal group meeting supported this recommendation.

Use of behavior intervention and positive reinforcement and guidance techniques have been used to address food refusal, gagging, and vomiting, as well as delays in feeding skills. Behavioral intervention with positive reinforcement and guidance techniques were used over a 2 – 14 week period in two patients with feeding problems of refusal, gagging, and vomiting (F.511). One patient responded well with an 80% increased food acceptance, and the other showed less improvement but both were reported to have a better quality of life. The positive reinforcement and guidance procedures used were effective in treating behavioral symptoms of food refusal, selectivity and inappropriate mealtime behaviors. This can improve food acceptance and help decrease need for tube feedings (F.511).

There were no statements in the Delphi surveys that addressed the use of behavioral intervention for individuals with PROP who have food refusal issues.

See Q#1 for nutrient recommendations to be met and the evidence and consensus to support them.

It has been recommended that nutrient intake be adjusted for individual tolerance, growth spurts and minor illnesses. Based on literature reviews and reports on clinical experience, the principle factors regarding oral intake included treatment with a low protein/high energy diet combined with: disease-specific amino acid mixtures that exclude the particular precursor amino acids with remaining amino acids from natural protein sources and enriched with vitamins and minerals;adequate fluids to maintain hydration; avoidance of fasting; increased kcals during illness to prevent catabolism; and maintenance of normal GI motility (F.534, F.3109, G.18, G.19, G.51, G.64, G.80).  In literature reviews, reports on clinical experience, and case reports/series, a diet restricted in the offending amino acids ILE, VAL, MET and THR based on individual tolerance and adequate growth and supplemented with medical food to meet the RDA for total protein, were reported to lead to more favorable outcomes as well as provide a good source of vitamins and minerals missing in a low protein diet (F.1387, F.3387, F.3399, F.242, F.502, G.18, G.51, G.67, G.80). Appropriate counseling on maintaining adequate energy and protein intakes in amounts required to prevent growth failure and allow for catch-up growth and maintenance of adequate nutritional status has been recommended, though specific outcomes for these recommendations were not provided (F.534).

Delphi 1:

There was consensus among all respondents (90% agreement) that the medical food and complete (intact) protein should be prescribed together in amounts needed to enhance anabolism.

Although the specific impact on metabolic stability has not been provided, several publications report the restriction of odd-chain fatty acids by avoidance of certain dietary sources including butter, cream, lard, olive oil, excess polyunsaturated fatty acids, and breads containing added sodium and calcium propionate. These reports also recommended avoidance of fasting which could lead to endogenous production of odd-chain fatty acids compromising metabolic control (F.597, F.3109, G.18, G.51, G.67, G.80). 

Delphi 1:

There was no consensus (56% RD and 0% MD respondents agreed) for recommending that polyunsaturated fats should be restricted in the diet.

Delphi 2:

There was no consensus (75% RD and 19% MD respondents agreed) for recommending the restriction of dietary intake of odd chain fatty acids on a routine basis.

There was no consensus (33% RD and 0% MD respondents agreed) for recommending that odd chain fatty acids should be restricted only during illness.

There was no consensus (17% RD and 36% MD respondents agreed) for recommending that odd-chain should never be restricted.

An individualized sick day home feeding plan can be used to manage individuals with mild illnesses, without GI symptoms and with urinary ketones "small" or less, if they maintain close contact with the metabolic care team. A home emergency feeding regimen was recommended, based on a literature review and two reports on clinical evidence, during mild illness without GI symptoms to provide adequate energy and prevent endogenous protein catabolism, and it was reported that this was done in consultation with the medical care team, though no clinical outcomes were reported (F.3399, G.19, G.20)

An individualized plan should be developed for the patient including a reduction of total protein from complete protein and medical food by ~50% for 24 – 48 hours, an increased energy intake from carbohydrates and fats, maintenance of adequate hydration, while monitoring clinical signs and symptoms and maintaining contact with the metabolic clinic as directed (F.3399, G.19, G.20).

Delphi 2:

There was consensus (at least 80% agreedment among all respondents) for 8 of 10 items of a home emergency management plan for non-acute illnesses (with negative or trace urinary ketones and no gastrointestinal symptoms). The two items about which there was no consensus were: the recommendation that (when protein intake has been limited), intact protein AND medical food should be introduced together (there was a 46% agreement among all respondents for this item); and the recommendation that total protein from both intact protein sources and from medical food be reduced by 50% (there was 54% agreement among all respondents for this item).

There was consensus (80% of RD and MD respondents agreed) that the family/individual information should be provided about monitoring for clinical signs and symptoms, advise the family/individual to contact the metabolic clinic when mild illness occurs, if urinary ketones are greater than 1+, the metabolic clinic should be contacted immediately, and the metabolic clinic should provide an individualized "emergency letter" to be used in the event of an emergency department visit.

Administration of more frequent feedings with smaller volumes has been recommended to aid enteral tolerance. Feedings were recommended to be made up of 10 – 25% carbohydrates from glucose polymer and 3.5 – 5% fat to provide 72 – 145 kcal per 100 ml from carbohydrates and fat, 120 – 150 ml/kg body weight/day or 1200 – 2500 ml total with amounts adjusted for age. In these reports, additional water was suggested whenever there were  intermittent febrile illnesses and/or increased stool losses and this could be  provided by continuous enteral feeds via tube feedings (F.3399, G.19, G.20).

Delphi 2:

There was consensus (80% of RD  and MD respondents agreed) that energy intake can be increased by 10-20% using carbohydrates and fats, fluids increased by 10-20% of usual intake, and to promote intake of energy and fluids by providing small, more frequent feedings

Restriction of complete protein has been recommended not to exceed 48 hours during mild illnesses. Based on clinical practice and published recommendations, caregivers can be instructed that they may reduce total protein intake by ≥50% per 100ml volume of medical food for 24 – 48 hours. Precursor-free amino acids may be provided at this time if the increased osmolarity can be tolerated but avoided if with hyperammonemia (F.3399, G.19, G.20).

Delphi 2:

There was consensus (88% of the RD and MD respondents agreed) that the duration of protein reduction should be for no more than 24 - 48 hours.

There was less agreement  to instruct the family/individual in the plan to reduce total protein from intact protein and from medical food by 50% (50% of RD and 57% of MD respondents) and that when protein intake has been limited that intact protein and medical food should be reintroduced together (42% of RD and 64% of MD respondents).

The following factors should be considered to determine the appropriateness of managing the mildly ill individual with PROP at home: patient’s age; severity of the illness; the caregiver’s ability to accurately report clinical status; patient’s history of previous illnesses and outcomes; time and distance to emergency medical assessment and treatment (F.3273; F.3399).  Pre-planning for illness management with an emergency medical treatment letter including contact information for patients’ metabolic clinic is recommended (F.3403). 

Delphi 2:

There was consensus (96% respondents agreed) to advise the family/individual to contact the metabolic clinic when mild illness occurs.

There was consensus (92% respondents agreed) that the metabolic clinic should provide an individualized "emergency letter" to be used in the event of an emergency department visit.

Respondent Comments: 1) This is all dependent on each pts course of illness. 2) Individualizing probably increases the risks if these are not updated. 3) Our opinion on best practice is to encourage communication between families and clinic during illness -- and decide together on best action to take. We do have concerns about families overusing "sick day" protocols (out of an understandable abundance of caution) and have seen marginal/deficient nutrient intakes when "sick day" formulas are used frequently.