Hyperammonemia

ABSTRACT. Background: Parenteral nutrition (PN) is an essential component of neonatal care for those infants who are unable to tolerate adequate enteral feeding. Its use is not without complications such as biochemical derangements, sepsis, thrombosis, extravasation of fluid, and death. Such complications can be reduced by meticulous management of PN in response to biochemical abnormalities, nutrition teams, policies to reduce sepsis, and staff training to be more aware of pericardial and pleural effusions. We ascertained the current practices in PN administration and management of complications in all neonatal units with 6 or more intensive care cots in England, Scotland, and Wales. Methods: Telephone survey of middle grade doctors (Specialist Registrars) working in all 57 neonatal units was conducted using a standard questionnaire. The questions were focused around practical issues and problems that are commonly encountered with PN practice, including composition, complications, and nutrition support. Results: A response was obtained from 95% of the units contacted and a wide range of practices observed. Thirty-three percent of units delay protein (nitrogen) until >48 hours after birth. Lipid infusions are stopped in proven or suspected sepsis in just over half of all units. In hyperglycemic preterm infants, 25 units decrease their glucose infusion, 21 commence insulin, and 8 have no policy. Two thirds of middle grade doctors had no idea of the amount of protein or nitrogen to prescribe for these infants, and only one-third involve a pharmacist in the PN prescribing. Conclusions: There is a diverse practice and knowledge with a concerning lack of education in nutrition among the middle grade doctors in England, Scotland, and Wales. The management of common complications such as sepsis and hyperglycemia are highly variable. Improved staff training and production of unified evidence-based guidelines need urgent consideration. (Journal of Parenteral and Enteral Nutrition 28:176-179, 2004)

The administration of parenteral nutrition (PN) is an essential component in neonatal intensive care. It is almost universal for infants

Although PN improves the nutritional state and promotes growth of very small neonates, it is not without risks, including sepsis,2,3 catheter-related complications,4,5 thrombosis, and many metabolic derangements, including hyperglycemia, cholestatic liver disease, hyperlipidemia, metabolic acidosis, hyperammonemia, and extravasation6 leading to pericardial, subdural, and pleural effusions, and occasionally death.

PN has existed in its present form for >30 years.7 Two recent areas of improvement include the prevention of complications and the further refining of nutritional needs in extremely preterm neonates. There are few national/international guidelines for administration of PN, and a number of controversies continue to exist in neonatal PN administration.8-10 These include the time of introduction of protein/nitrogen and lipids after birth, the safe maximum concentration of protein or nitrogen necessary for promoting effective growth, situations when lipids or protein or nitrogen need to be stopped, and the effective management of hyperglycemia.

Multidisciplinary nutrition care teams have been shown to reduce PN complications,11,12 and a trained staff member prescribing PN is essential. The ideal prescription is by a doctor working closely with the PN pharmacist using electronic technology. Administration by appropriately trained nursing staff reduces sepsis considerably.13,14

Objective

We wanted to ascertain the current practices in PN administration and management in all neonatal units with 6 or more intensive care cots in England, Scotland, and Wales.

MATERIALS AND METHODS

All neonatal units in England, Scotland, and Wales with 6 or more intensive care cots were identified from the Directory of Emergency and Special Care Units 2000. A standardized questionnaire was devised for administration by phone. The telephone questionnaire survey was performed in January and February 2002 by single observer (MA) contacting the neonatal middle grade doctor (Specialist Registrar) in each unit. Repeated telephone calls were made if the registrars were busy or unable to reply on first occasion. The questions were focused around practical issues and problems that are commonly encountered with PN practice, including composition, complications, and nutrition support. The questionnaire is shown in Figure 1.

RESULTS

All 57 neonatal units with 6 or more intensive care cots across England, Scotland, and Wales were approached. A response was obtained from 95% (54/57) of the units, which included 43 of 45 in England, 6 of 7 in Scotland, and 5 of 5 in Wales.

The first question concerned the introduction of protein or nitrogen and lipids in a 28-week-gestation male infant weighing 1.1 kg. Twenty-four percent of the units commence protein or nitrogen soon after birth (0-23 hours), 43% between 24 and 48 hours, and 33% after 48 hours of life. Similarly, 6%, 48%, and 46% of neonatal units start lipids soon after birth (0-23 hours), 24 to 48 hours, and >48 hours respectively. Table I shows the sources of protein or nitrogen and lipids. The most commonly used protein or nitrogen source was Vamin (23/54; Pharmacia), a protein solution customized toward providing the most physiologic amino acid profile to neonates. Most common lipid source was Intralipid 20% (45/54; Kabutrum Inc., California and Stockholm) which is an oil-in-water emulsion manufactured from soya bean oil. Almost all the middle grade doctors were unaware of the concentration of nitrogen used in the PN, and two-thirds of them (35) were unaware of the concentration of protein used in PN in their unit. The third that were aware stated that the maximum concentration of protein used was 3 g/kg per day (6 units), 2.5 g/kg per day (12 units), and 2 g/kg per day (1 unit).

Common indications to stop lipids in PN (Table II) were confirmed sepsis (19), suspected sepsis (10), raised liver enzymes twice the upper limit of normal or more (9), conjugated hyperbilirubinemia >20% of total bilirubin (6), low platelets,

In the hypothetical case of an infant with hyperglycemia (laboratory blood glucose >12 mmol/L or 216 mg/dL) along with glycosuria while receiving 150 mL/kg per day of 15% dextrose PN, 25 of 54 units would decrease the concentration of glucose in the PN, whereas 21 of 54 units commence insulin infusion and 8 have no policy (Table III).

Table IV shows the person responsible for ordering PN. Only 16 of 54 (30%) units have direct involvement of a pharmacist to order PN. All units (54/54) have a standard unit protocol for PN. Most units (70%) do not have regular formal input from nutrition or feeding team.

DISCUSSION

To the best of our knowledge, this is the first study looking at the practice of PN administration in neonatal units across England, Scotland, and Wales. Not surprisingly, our results show a diverse practice and knowledge of this, with a concerning lack of education of the middle grade doctors (Specialist Registrars) in nutrition. We tried to include all neonatal units with 6 or more intensive care cots, who would perform regular PN administration. The response rate obtained was excellent (95%).

In a study of 18 exclusively parenterally fed preterm infants, earlier administration of amino acids on day 2 vs more than day 4 resulted in higher protein flux and a higher protein synthesis rate.15 Another randomized study comparing 3 parenteral regimens (glucose 10% only, glucose 10% with amino acids, and glucose 10% with amino acids and lipids) administered during the first 48 hours of life demonstrated that significant potential gains were achieved from giving total PN to low-birth-weight infants immediately after birth.16 This study suggested that significant metabolic disturbances in preterm infants may be prevented by starting regimens of IV amino acids and lipid shortly after birth. Studies in the low-birth-weight infants, which tested more aggressive protocols, have demonstrated a positive response to amino acids and lipids from the first day of life, with evidence of improved nitrogen balance and growth.17-20 A third of United Kingdom units delay protein administration for 48 hours, and half defer lipids till then. A positive nitrogen balance, and thus the achievement of an anabolic state, can occur with parenteral lipid or glucose caloric intakes of 60 kcal/kg per day and amino acid intakes of 2.5 to 3.0 g/kg per day. With a higher nonprotein caloric intake of 80 to 85 kcal/kg per day and amino acid intakes of 2.7 to 3.5 or 3.85 g/kg per day, nitrogen retention occurs at the fetal rate.21 Whether a more aggressive approach will ultimately decrease neonatal morbidity or result in a shortened hospital stay along with medium and longterm benefits remains to be determined.

Only a third of the neonatal middle grade doctors responsible for prescribing PN were aware of the desirable protein level despite the potential harmful effects of excess protein or nitrogen administration (ie, hyperaminoacidemia), which is implicated in subsequent neurodevelopmental delay.22

Our respondents found the question on "clinical situations/indications to stop lipids in PN" difficult to answer (Table II). There are often multiple factors that need consideration in a particular situation (eg, how "unwell" is the infant with thrombocytopenia?) and often an individual consultant's practice. There is a spectrum of hepatobiliary complications associated with PN, including abnormal liver function tests, steatosis with hepatomegaly, steatohepatitis, and even progression to chronic liver disease. In a study of 46 neonates requiring PN for >14 days at a neonatal surgical intensive care unit, significant factors leading to the development of PN-associated cholestasis were low birth weight, duration of PN administration, the interval before enterai feeding was initiated, sepsis, central venous catheter infection, and the number of operative procedures.24 In a multivariate analysis of 62 very low-birth-weight infants who received PN, the longer duration of PN and the maximum daily amino acid in infusate were found to be independent variables predictive of development of cholestasis, in addition to other significant factors like duration of fasting and incidence of necrotizing enterocolitis.25 The incidence of PN-related liver disease may vary from 7% in infants with birth weight of 1500 to 2000 g up to 50% in infants weighing

Differences in practice also exist in the clinical situation with hyperglycemia (laboratory blood glucose of >12 mmol/L or 216 mg/dL) along with glycosuria while receiving 15% dextrose PN at a rate of 150 mL/kg per day (Table III). Thirty-nine percent of respondents replied that they would use insulin infusion in the first instance so as not to compromise the caloric intake, whereas 46% would decrease glucose concentration in the PN. However, this may not reflect the individual unit policy as many also commented that it depends upon the consultant on call at that time. In addition, other factors such as the cause of hyperglycemia (eg, sepsis or necrotizing enterocolitis, clinical condition of the neonate, along with the need for increased caloric requirement and the duration of PN) are also thought to be important in decision making. In a study of 20 very low-birth-weight infants receiving PN (with mean of 27 weeks gestation), normoglycemia was maintained during reduced glucose infusion (from 10 mg/kg/min to 3 mg/kg/min for 7-11 hours) by glucose production primarily derived from gluconeogenesis, with glycerol being the principal gluconeogenic substrate.28

It is interesting to note that only 16 of 54 (30%) units regularly have nutrition or feeding team ward rounds on a weekly basis. We expected a higher percentage of units having regular input from feeding teams ideally consisting of a consultant pediatrician or neonatologist with an interest in nutrition, consultant pediatric gastroenterologist, pediatric dietitian, speech and language therapist, pediatric pharmacist, and a nutrition liaison nurse. These have been shown to reduce complications and sepsis rates.11

CONCLUSIONS

Our study has shown a wide variation in practice and knowledge, with a concerning lack of education in nutrition among the middle grade doctors (Specialist Registrars) in England, Scotland, and Wales. The management of common complications such as sepsis and hyperglycemia are highly variable.

We suggest that the involvement of nutrition teams in all neonatal units would help reduce PN complications. There is a need for further training of junior doctors in prescribing of PN along with the involvement of pharmacists to ensure safety. In addition, production of evidence-based unified guidelines for PN in neonatal units across the United Kingdom is urgently required.

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Mansoor Ahmed, MRCPCH[dagger]; Sarah Irwin*; and David P. Tuthill, MRCPCH[dagger]

From the [dagger]Department of Neonatal Medicine, Llandough Hospital, Cardiff, Wales; and *Pharmacy Department, University Hospital of Wales, Cardiff, Wales

Received for publication October 29, 2003.

Accepted for publication February 3, 2004.

Correspondence: Dr M. Ahmed, 6 Dale Avenue, Cardiff United Kingdom, CF14 4QQ. Electronic mail may be sent to mansoorlmc@hotmail.com.

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