The importance of increasing energy intake via calorically dense feeds is exhibited in 11 clinical studies (F.104, F.44, F.73, F.77, F.20, F.105, F.51, F.76, F.81, F.52, F.426) and 4 expert opinions (G.50, G.39, G.27, G.82). Energy recommendations indicated the following: 95 -150 Kcal/kg (neonates) (F.105, F.104, F.51, F.52), 1500 Kcal/m² (neonates and children) (F.73), 88 Kcal/kg (children) (F.76), and 150 to 200% of calculated energy needs (F.426)

In patients with MSUD who are hospitalized due to acute illness, energy recommendations are increased to up to 150% of the amount provided to the patient when well.

Evidence: Insulin was utilized to maintain blood glucose < 150 mg/dL (F.104) or 180 to 270 mg/dL (F.86) when pushing IV glucose. Studies reported a range of 0.04 to 0.13 U insulin per hour during surgery (F.127) and 0.05 to 0.3 U per hour during acute illness (F.44, F.75, F.426).

To allow sufficient glucose infusion for anabolism, insulin may be required to prevent hyperglycemia: although 71% agreed or completely agreed with this recommendation, comments of dissenters indicated that this recommendation should be reworded to state “insulin may be needed.” Specific comments pointed out need for blood glucose monitoring and individual assessment. Another indicated that insulin would be needed when blood glucose > 150 mg/dL”.

A common finding during illness is dehydration and acid-base imbalance (F.80, F.45, F.85). A solution of 5 to 10% glucose was recommended to treat dehydration and correct acidosis (F.104, F.51, F.81) in 3 reports. A fluid intake of 150 ml/kg has been recommended (F.81). Caution must be taken to avoid fluid overload and cerebral edema by monitoring and adjusting electrolytes (F.85, F.426, F.423, G.47).

• Careful monitoring of hydration, electrolytes and neurological status is necessary to prevent cerebral edema: 100% of respondents either agreed or completely agreed. Mannitol and hypertonic saline may also be required.

• IV fluids with 10% glucose should be provided at 1.5 – 2 times maintenance: 91% of dietitians and 83% of physicians either agreed or completely agreed. Comments/suggestions were added that: 2 times may be too much; need to monitor sodium: water balance; risk of brain edema is so great that need to evaluate carefully to determine if need fluid restriction; need intralipid 20% to meet remaining caloric needs; and may need higher % dextrose to reverse catabolism.

The majority of the articles cited below recommend a BCAA-free source of protein during acute illness however, recommendations vary in regard to the amount of BCAA-free protein. Age of the person, presenting symptoms and severity of symptoms seem to be determining factors. Ten clinical reports (F.104, F.44, F.45, F.73, F.20, F.105, F.51, F.76, F.75, F.426) and three expert opinions (G.50, G.39, G.82) recommend use of a BCAA-free source of protein. The total amount of BCAA-free protein ranged from 1.0 to 4 g/kg/day (F.44, F.73, F.105, F.51, F.76, F.426, F.423). Currently available BCAA-free medical foods are listed in Table TABLE #11, Classification of Medical Foods for MSUD

In patients with MSUD who are hospitalized due to acute illness, the amount of BCAA-free formula should be increased to 120-150% of the amount provided to the patient when well. The rationale for increasing BCAA-free formula is not only to replace the BCAA-containing protein (which is eliminated from the diet in acute illness) but also to maintain or increase energy intake to suppress catabolism and ketoacidosis.

Route of feeding: Both enteral and parenteral nutrition are used in the acute stage and during illness to aggressively supply needed calories to minimize catabolism. Twenty clinical reports (F.104, F.44, F.80, F.45, F.73, F.79, F.20, F.93, F.105, F.51, F.76, F.81, F.52, F.75, F.426, F.423, F.86, F.92, F.66, F.83) and 5 expert opinions (G.50, G.39, G.33, G.27, G.82) use enteral nutrition or a combination of enteral and parenteral nutrition management during acute illness. The decision regarding route and composition of solution/formula is based upon severity of symptoms at initial presentation or during acute illness. Length of intravenous therapy depended on the individual’s ability to tolerate formula by mouth or nasogastric tube. Enteral nutrition using a BCAA-free formula along with parenteral glucose and lipid solutions is used until total requirements can be met enterally. Specialized BCAA-free parenteral solutions were used in 2 reports (F.104, F.51). The specialized solution in one report was 9% BCAA-free amino acids and 20 to 25% glucose or 9% BCAA-free amino acids plus 10% glucose and 10 to 20% fat emulsion (F.104).

• Parenteral nutrition providing adequate BCAA-free amino acids, glucose and lipids should be prescribed for comatose patients: 77% of respondents agreed or completely agreed. There were several comments indicating a preference for using the gut if possible, or a combination or enteral and parenteral. One site uses an enteral amino acid mixture because they cannot keep BCAA-free TPN in stock; another stated that they do not use BCAA-free solutions for treatment. Other comments were: it is important to provide BCAA as soon as patient can tolerate to prevent catabolism and monitor carefully at this point, add ILE and VAL as indicated.

• 20% intralipid should be provided at 2 g/kg/day: while 100% of physicians agreed or completely agreed with this, 55% of dietitians agreed or completely agreed. Their comments were: increase lipids as able to maximize calories, base on kcal to provide approximately 50% of requirement, and depends on the fluid and dextrose in the TPN. Aggressive treatment with glucose and lipid in the first hours of illness is often necessary as acquiring the specialty TPN solutions may take at least 24 hr.

• Enteral feeding, total or partial, should be introduced as soon as possible: 100% of respondents either agreed or completely agreed.

For individuals with MSUD who are at risk for metabolic crisis, it is important that access to stat monitoring for acid-base balance (F.104), blood glucose (F.104), and indicators of cerebral edema be available (F.51, G.35, G.43, G.44)). There should be access for rapid turnaround for plasma amino acid analyses to follow BCAA (F.75, F.104) and frequent monitoring of urinary α-ketoacids (G.44). Although there is no published evidence for optimal intervals for monitoring, there are recommendations for every 2-24 hours for plasma BCAA (F.104), every 30-60 minutes for glucose when insulin is being given (F.104), every 6-24 hours for α- ketoacids (G.38). If hemofiltration is necessary, blood gas, hematocrit, total protein, sodium, calcium, phosphorus, urea, and creatinine should be monitored every 3-6 hours and amino acids every 12 hours (F.73). Inpatient treatment with possible admission to the critical care unit can facilitate monitoring of clinical signs as well as biochemical markers during serious catabolic illnesses

Consensus through both Delphi surveys and the Nominal Group stress the need for frequent clinical assessment and biomarker monitoring during catabolic illness.

• Use of hemofiltration: Dialysis or hemoperfusion was described in 15 clinical reports. (F.104, F.45, F.73, F.79, F.20, F.93, F.105, F.52, F.85, F.75, F.91, F.423, F.86. F.92, F.66). Dialysis was recommended in one report when plasma LEU was > 2000 µmol/L (F.104). Another report used the LEU level of >1500 µmol/L to initiate hemofiltration (F.423). 
• Continuous venovenous extracorporeal removal therapy was recommended when two out of three of the following were present: plasma LEU >1700 µmol/L, comatose state, gastrointestinal intolerance or danger of severe brain damage (F.73). Worsening neurological signs, despite appropriate nutritional therapy, was another indication for use (F.79, F.93).
• Dialysis is not often necessary for patients with MSUD because acute illness resulting in elevated plasma LEU can usually be well-managed using BCAA-free feedings (either enteral or parenteral), nutrition support to provide increased energy and supplemental ILE and VAL (G.50, G.43, F.51).

• Aggressive nutritional support including energy, fluid and BCAA-free amino acid mixtures should be used in conjunction with hemodialysis, peritoneal dialysis or exchange transfusion: 100% of respondents either agreed or completely agreed.

• Supplemental ILE and VAL: ILE and VAL supplementation during acute illness is used to help decrease LEU levels into normal treatment range by providing substrate for protein synthesis and to prevent ILE and/or VAL deficiencies. This is supported by 8 clinical reports (F.104, F.44, F.73, F.51, F.76, F.75, F.426, F.83) and 5 expert opinions ( G.50, G.39, G.33, G.27, G.82). The amount of supplemental ILE and VAL varied, from minimal daily requirements (F.104), 7 - 15 mg/kg (F.76) to 80 - 300 mg/day (F.44, F.73, F.51, F.81, F.52). When managing infants and children with severe decompensation, F.73 gave 150-300 mg/day of ILE and VAL if plasma levels were below 100 µmol/L.
• Use of other amino acids: One clinic reports that glutamine and alanine (250 mg/kg/day each) have been utilized to promote LEU incorporation into protein for the sick neonate (F.51) and when plasma concentrations of tyrosine, histidine or threonine have been low, supplements of these amino acids have been recommended to normalize plasma levels (F.51).

There was strong agreement that ILE and VAL supplementation should be used to help decrease LEU levels during illness. If patients normally receive supplementation, this should be continued, and may be increased during illness.

Reintroduction of dietary intact protein (or LEU source): LEU is typically stopped during initial presentation and acute illness depending on symptoms. Seven clinical studies (F.104, F.105, F.51, F.426, F.83, F.75, F.44) and 3 expert opinions (G.50, G.39, G.33) recommend to reintroduce dietary LEU when plasma LEU reaches the upper level of treatment range or when metabolic decompensation is abated. This can usually be accomplished within 48-72 hours (F.104, F.51). Minimal details are provided that recommend the amount of dietary LEU that should be introduced. Recommended ranges of protein, energy and BCAA are found in TABLE #3, Nutrient Recommended Intake and Sources in the Dietary Treatment of Well Individuals with MSUD.

• LEU from intact protein or amino acid mixtures should be introduced when plasma levels fall to the upper limit of accepted treatment range: 59% of respondents either agreed or completely agreed, with the dietitians at only 46% agreement. Comments included: introduce sooner/may need longer; individually assess based on other indicators of catabolism; also based on the time passed without natural protein—usually begin ¼ usual goal for 24 hr and increase by ¼ to full goal both with time (24 hr), blood levels and/or DNPH.
• In patients with MSUD who are hospitalized due to acute illness, LEU (intact protein) should be re-introduced (slowly) by 48 hours: 100% of respondents agreed.
• ILE and VAL supplementation should begin when plasma concentrations fall to the upper limit of the accepted treatment range: 59% of respondents agreed or completely agreed. Three who did not agree commented that they would start supplementation sooner.

Although the use of human breast milk has been reported in the dietary management of a number of IMD, there are only two publications (F.664, F.663) that provide any outcome data for infants with MSUD. One study reports the results of a survey of 27  IMD centers in 15 countries (caring for over 8000 patients with IMD treated through dietary intervention). Successful demand feeding was reported in 17 infants with MSUD. The study did not report the percentage of breast feeding failures, but listed the most common problems incurred for the total population of IMD cases attempting breast feeding. The authors recommended strict monitoring, but did not feel their data suggested what the appropriate monitoring intervals should be (F.664). Another study reported the experience of breast milk feeding among seven patients with IMD, including a single patient with MSUD. Expressed breast milk was used for 2 months. Then, after one week of on-demand feeding, plasma BCAA levels were too high. On-demand breast feeding was attempted again at 3 months with good control, but was terminated because of the stress of frequent monitoring (F.663).

• Mature human breast milk with approximately 1 mg LEU/mL is an appropriate source of intact protein for infants with MSUD: 100% agreement among RDs, 83% among MDs

• Bottle feeding a combination of expressed breast milk and BCAA-free medical food requires determining the requirements for PRO, BCAA, energy and fluid for the infant with MSUD, and adjusting the mixture frequently based on anthropometric and biochemical monitoring: 100% agreement among both RDs and MDs

• Alternating between feeding at the breast and from the bottle (containing the BCAA-free medical food and any additional supplemental VAL, ILE and energy) can be successful if the infant with MSUD has close biochemical and anthropometric monitoring: 92% agreement among RDs, 67% among MDs.

Two reports (F.20, F.426), one review (F.83) and four expert opinions, (G.26, G.33, G.44, G.27) provided interventions to be used in non-critical illness. Sick day regimens included removal of natural protein for 1- 2 days with gradual increase to 1 g/kg plus energy intake of 100 to 170 kcal/kg (F.20, F.426). Oral glucose solutions are recommended to increase energy intake. The use of nasogastric feeding is recommended if the individual is unable to consume adequate intake orally (F.83). Specific emergency guidance for caregivers and ED personnel are also recommended (G.44)

• Guidelines for “sick day, at home” management: 100% agreed or completely agreed that the guidelines should:
  • Be individualized
  • Include appropriate guidelines for monitoring α-ketoacids and clinical status
  • Include appropriate guidelines for decreasing BCAA intake
  • Include appropriate guidelines for maintaining fluid and energy intake
  • Include emergency contact information
• There was 100% agreement that intact PRO should be reduced by 50-100% for at least 24 hours with replacement by BCAA-free medical food and additional energy sources.