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1

Ketogenic Parenteral Nutrition

for

Children with Drug Resistant Epilepsy

Recommendations for safe & effective application

October 2018

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Project group: - Elles van der Louw, RD, Erasmus MC- Sophia Children's Hospital, University Medical Center

Rotterdam, the Netherlands.

- Vanessa Aldaz, RD, Rady Children's Hospital, San Diego, USA.

- Jessica Harvey, RD, Cincinnati Children's Hospital, Cincinnati, USA.

- Marian Roan, RD, UCSF Benioff Children's Hospital, Oakland, USA.

- Dorine van den Hurk, RD, University Medical Hospital Utrecht Wilhelmina Children’s Hospital,

Utrecht, the Netherlands.

- Prof. Dr. Helen Cross, The Prince of Wales’s Chair of Childhood Epilepsy and Honorary

Consultant in Paediatric Neurology at UCL Great Ormond Street Institute of Child Health, and

Great Ormond Street Hospital for Children NHS Trust, London, UK.

- Prof.Dr. Stéphane Auvin, Pediatric Epilepsy & Child Neurology Paris-Diderot University, Paris,

France.

In close cooperation with a review group:

- Baheerathi van de Bor, RD, UCL Great Ormond Street Hospital for Children NHS Trust,

London, UK.

- Dr. Anastasia Dressler, Universitätsklinik fur Kinder-und Jugend heilkunde

Pädiatrisches Epilepsiezentrum, Vienna, Austria.

- Eimear Forbes, RD, Temple Street Children's University Hospital, Dublin, Ireland.

- Prof. Dr. Joerg Klepper, Klinikum Anchaffenburg-Alzenau, Germany.

- Dr. Joanne Olieman, RD, Erasmus Medical Center Sophia Childrens Hospital

Rotterdam, the Netherlands.

- Venetia Simchowitz, clinical pharmacist, UCL Great Ormond Street Hospital for Children

NHS Trust, London, UK.

- Dr. Thomas Storme, Pharm D, Pharmacy Department, Hoptial Robert Debré, Assistance

Public Hȏpitaux de Paris, Paris, France.

We would like to thank Prof. Dr. Eric Kossoff for critically reviewing this manuscript.

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Table of contents

Introduction 6

Chapters

1. Current usage of Ketogenic Parenteral Nutrition in the world 7

2. Parenteral Nutrition in Children: a brief introduction and definition 8

3. Ketogenic Diet Therapy in drug resistant epilepsy: a brief introduction of 10

indications/contra indications an practicalities concering Parenteral

administration.

4. Preparing for Parenteral Nutrition administration during Ketogenic Diet 14

Therapy.

5. The Ketogenic Parenteral Nutrition prescription 18

6. Treatment phase 35

7. Evaluation 45

8. Weaning Parenteral to Enteral Ketogenic Diet 46

9. Conclusions 49

Funding and Disclosures 50

Appendices 51

References 69

4

Table of abbreviations: ASPEN American Society for Parenteral and Enteral Nutrition

BMR Basal Metabolic Rate

CVC Complications of central Venous Catheters

ESPEN European Society for Clinical Nutrition and Metabolism

ESPGHAN European Society for Paediatric Gastroenterology Hepatology and Nutrition

EFAD Essential Fatty Acid Deficiency

FDA Federal Drug Administration

FIRES Febrile Infection Related Epilepsy Syndrome

FO Fish Oil

GI Gastro Intestinal

GIR Glucose Infusion Rate

GLUT1 DS Glucose Transporter Deficiency type I

ICU Intensive Care Unit

IFALD Intestinal Failure Associated Liver Disease

ILVEs Intravenous Lipid Emulsions

ISMP Institute for Safe Medication Practices

IV Intravenous

IVLE Intar Veinous Lipid Emulsion

KD-PN Ketogenic Parenteral Nutrition

KDT Ketogenic Diet Therapy

NPO Nihil per os (i.e nothing oral)

PDHC Pyruvate DeHydrogenase Complex deficiency

PEG Percutaneous Endoscopic Gastrostomy

PN Parenteral Nutrition

RDA Recommended Daily Allowance

REE Resting Energy Expenditure

RSE Refractory Status Epilepticus

SMOF Soybean oil, Medium Chain triglycerides, Olive oil ,Fish oil

TPN Total Parenteral Nutrition

5

"The ketogenic diet is heading into new, previously uncharted territories. The concept of dietary

management of emergency situations, specifically super-refractory status epilepticus, is one of the

most exciting and fastest-growing topics in the ketogenic community. In just 10 short years, the use

of ketogenic diet therapy for status epilepticus has progressed from sporadic case reports to now

sufficient evidence to be listed in our 2018 international ketogenic diet consensus statement as an

"indication". Intensive care units are asking for our help to start and maintain ketogenic diets more

than ever before.

But with this strong interest comes an equally powerful realization that we need logical, rational,

evidence-based guidelines to provide assistance for these critically-ill patients. Many of them are

unable to receive ketogenic diet therapy enterally and, at least temporarily, require keto "TPN". This

book is an excellent first step to guide this practice, written by ketogenic diet experts, including

neurologists and dietitians from all over the world. Each chapter includes expert consensus

guidelines, survey-based results, as well as data gleaned from the 35 cases published to date. The

hope is that this book will lead to multicenter protocols followed by prospective clinical trials in this

growing field. I look forward to reading the second edition!"

September 2018

Eric Kossoff, MD, Johns Hopkins Hospital, Baltimore, USA

6

Introduction

Ketogenic Diet Therapy (KDT) is a dietary treatment with an established efficacy in children and

adolescents with epilepsy [1]. Ketogenic diet therapy is mostly used in case of drug resistant epilepsy

with a significant responder rate defined as at least 50% seizure reduction, seen in approximately

50% of those started on it. The KDT is also the treatment of choice in some metabolic disorders, in

particular GLUT1 deficiency syndrome (GLUT1 DS) and pyruvate dehydrogenase deficiency (PDHC)[2-

5] .

There are multiple ways to conduct the KDT. In most cases, the KDT is given by an enteral diet that is

tailored to each individual. It requires careful and detailed calculation of the nutritional composition

to ensure adequate growth and prevent deficiencies [1]. The KDT has different ratio's (ketone

producing component fat versus non-ketone producing components protein plus carbohydrates)

which are individualized according to tolerance and ketosis, with most children starting on a 3:1 or

4:1 ratio. The KDT can also be provided as an enteral formula given by nasogastric tube or

Percutaneous Endoscopic Gastrostomy (PEG) when required.

In some rare conditions such as Refractory Status Epilepticus (RSE) or Febrile Infection Related

Epilepsy Syndrome (FIRES), the KDT needs sometimes to be provided by intravenously (parenteral

route). This would be the case in the acute setting with temporary digestive dysfunction or more

rarely, in case of chronic digestive dysfunction. Intensive care units will request to start KDT and

dietitians are then forced to consider how best to provide this in the setting of a non-functional

gastrointestinal system.

There are currently limited data available and no consensus on how to initiate, conduct and follow

the administration of ketogenic parenteral nutrition (KD-PN). An international group of experts has

worked together to provide a consensus for KD-PN. The aim of these recommendations is to give

guidance to a safe application of KD-PN based on evidence from literature combined with expert

opinions. These recommendations have been established by an international group of experts and

are based on consensus.

Application of these Ketogenic parenteral recommendations in medical practice have to be

tailored to the medical protocol of each individual expert center.

We strongly recommend that centers implementing KDT parenterally have experience in

enteral use of the KDT as well.

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Chapter 1. Current Usage of Ketogenic Parenteral Nutrition in the

world: why is this document necessary?

By Jessica Harvey

The Ketogenic Diet Therapy (KDT) is undertaken in order to reach and maintain a state of ketosis

through dietary modification. Urinary and blood ketones are used as the marker of compliance and a

metabolism shift by using KDT . Most commonly, this diet is consumed by an enteral route (by

mouth or by a naso-gastictub/ PEG) and started as an elective admission at the request of parents

and neurologists to reduce refractory seizures. Some patients requiring a KDT are unable to receive

nutrients through the intestinal tract related to an acute condition or chronic illness. These patients

may require administration of the KDT via parenteral nutrition. The goal of intravenously

administering the KDT is to maintain ketosis, continue seizure control, with minimal to no adverse

effects. Published data regarding the efficacy of the ketogenic diet when administered parenterally

are limited primarily to single case reports and series [6-14]. To date there are currently no

recommendations regarding the safety and efficacy of the short or long term use of the ketogenic

diet delivered parenterally.

At the 5th International Ketogenic Symposium in Banff, Canada in 2016, a group of experts on

ketogenic diet gathered together to discuss the need for established guidelines for KD-PN. Many

ketogenic centers throughout the world currently have a protocol for KD-PN they use in their own

setting. Therefore, the decision was made to create an international survey to gather information on

how centers administer KD-PN and to what degree there is commonality. This survey was distributed

to Registered Dietitians working in the area of KDT throughout the world who were member of the

Keto RD Listserv. The goal was to obtain specific information on KD-PN that could be used to

formulate recommendations and identify topics for further research. Twenty-four centers from nine

different countries (Canada, Denmark, England, France, Germany, Ireland, the Netherlands, Sweden

and USA) responded to the survey.

In addition, a literature search was undertaken and identified existing published research (35

individual patients [6-14]).

The survey reported that 70% of respondents provide between 0-3 KD PNs per year, and 30% provide

approximately 4-10 KD-PNs per year. There were variable results on how each center prescribes

calories, dextrose, protein, and lipids in the parenteral solution and various ways of increasing each

component to goal prescription. Many respondents (69%) will start KD-PN in settings (i.e: surgical

floor for a post operative ileus, bowel rest, or intercurrent illness), other than critical care (i.e.

refractory status epilepsy). Forty-five % of the responders would start KD-PN if the patient has been

nihil per os (NPO) for more than 72 hours and 55% starts KD-PN earlier. The type of intravenous lipid

emulsion varied between SMOF lipid 20%® and Intralipid 20% ®, which are different in combination

of lipids (fat origin).

8

Chapter 2. Ketogenic Diet Therapy in drug resistant epilepsy: a brief

introduction of indications/contra indications and

practicalities concerning parenteral administration. By Stéphane Auvin.

Ketogenic Diet Therapy (KDT) is an established treatment for drugresistant epilepsy with several

randomized controlled trials and numerous open labelled studies [15]. About 40-50% of the patients

experience a 50% reduction of seizure frequency. ). In the recent years, the use of the KDT for

refractory status epilepticus (RSE) and FIRES has been increasingly reported [16, 17]. In addition to

the open-studies and the case-reports, there is a phase 1-2 trial establishing the safety and the

feasibility of the use of KDT in adult patients with RSE [18]. Among the RSE, the KDT might have a

particular efficacy in case of Febrile infection-related epilepsy syndrome (FIRES)[16, 19]. In the 2018

ketogenic diet consensus statement, it is listed in Table 1 as an “indication” for KDT based on the

growing body of evidence (1).

To date there are 35 reported patients that have been treated with KDT parenterally (Table 1). In

most cases, the use of KD-PN was only for few days. The KD-PN was followed by enteral

administration of KDT. The use of PN was related to acute illnesses resulting in intestinal ileus, severe

vomiting or severe diarrhea. Few cases have reported prolonged use of parenteral KD due to

conditions in which the use of the enteral route was challenging [11].

There is currently no data allowing a real evaluation of the level of efficacy of parenteral compared to

enteral administration of the KDT. The available data from 35 reported patients (Table 4) show that

parenteral KD allows the patient to reach a state of ketosis, which is a hallmark of the use of KDT and

possibly correlates with efficacy. There are also data reporting the experience of various teams to

initiate KDT by parenteral administration switching to enteral administration of KDT after a few days

(Table 4).

The use of KD-PN may lead to complications such as hypertriglyceridemia, increase of pancreatic

enzyme levels and increase of liver enzyme levels. The exact significance of these changes is not

established and whether these are transient or long term. These parameters should be carefully

monitored and actively managed (see Chapter 6).

We assume that the use of KDT by parenteral administration is associated with the same risk of a

regular total parenteral nutrition (TPN) such as sepsis and catheter thrombosis.

Parenteral administration of KDT should be omitted to the group of newborns and preterm infants as

they are a high risk group for malnutrition and complications.

9

Table. 1 Overview of studies and indications.

Based on the previous information the following recommendations were formulated:

RECOMMENDATIONS on indications/contra indications KDT and/or PN.

Number of patients

Indication Duration Adverse events Type of Lipid solution

Rosenthal E, et al (1990) [6]

1 GI problems during KDT

4 months Sepsis at 4 months Clintec Nutrition®

Roan, M. (2011) [7]

1 GI – Protein-losing enteropathy during KDT

12 months (with minimal EN)

No Intralipid® 20%

Jung, J et al (2012) [8]

10 GI problems during KDT

4.1 (mean) Range (2.6-5.6 days )

- All: hyper triglyceridemia - n=1: pancreatic Enzymes - n=1: increased ASAT/ALAT

Lipision® 20%

Strzelcyk A et al (2013) [9]

1 SE - Tube not tolerated

27 days Not reported Lipofundin® 20%

Lin J J et al (2015) [10]

1 SRSE - GI (bleeding)

8 days (5 exclusive TPN)

-Hyper-triglyceridemia -Increased pancreatic enzymes

SMOF Lipid® 20%

Chiusolo F et al (2016) [11]

1 RSE-GI 8 days (3 exclusive TPN)

Intralipid® 20%

Appavu B et al (2016) [12]

1 RSE Not available No Not available

Farias-Moeller, F. et al (2017) [13]

2 RSE 15 days 8 days

-Hypertrigliceridemia, HLH -Hypertrigliceridemia, pancreatitis

Not available

Dressler,A et al (2017) [14]

17 SE n= 3 GI n=15 13/17 already on KD

3 days (IQR 2– 4 days) (range 1– 41 days)

-n=3:transient hypertriglycerides -n=5: hypercholesterol -n=1: transient GGT -n=1: GOT -n=1: GPT -n=1: LDH

Intralipid® 20%

Clinoleic® 20%

SMOF lipid® 20%

The indications of the KDT should be similar for parenteral use as for enteral diet use of KDT

(newborn and preterm infant excluded). The most common uses reported to date include

temporary NPO situations and refractory status epilepticus. Based on the risk-benefit ratio, all the

efforts should be undertaken to try to use the enteral route before considering a parenteral use

of KDT. In addition, once KDT-PN has started, the patient should be regularly reassessed to

determine if enteral KDT can be restarted.

10

Chapter 3 Parenteral Nutrition in Children

By Vanessa Aldaz, Elles van der Louw.

General The purpose of parenteral nutrition (PN) is to correct or prevent nutritional deficiencies when

adequate enteral nutrition is precluded by impairment or immaturity of gastrointestinal function [20]

it is used to treat children that cannot be fully fed by oral or enteral route. Intestinal failure occurs

when the gastrointestinal tract is unable to ingest, digest and absorb sufficient amounts of

macronutrients, electrolystes and/or water to maintain health and growth. Parenteral nutrition can

be used as TPN or additional to enteral nutrition and can be used not only for patients who require

short-term parenteral feeding but also on a long-term basis in case of chronic intestinal failure [21].

Parenteral nutrition is usually started when an infant or child is not able to receive enteral feeding for

more than 48 hours [21-23]. For older children, depending on the underlying disease, phase of

illness, and nutritional status, this might be postponed. A large multicenter trial of > 1400 critically ill

children shows beneficial effects of late start of PN (after a week) versus early start of PN based on

modulation of the neuro endocrine stress respons and the process of autophagy [24].

Parenteral Nutrition is considered a high-alert medication by the Institute for Safe Medication

Practices (ISMP). Therefore, ensuring safe indications and safe compounding of PN solutions in

hospital and home setting requires skilled and knowledgeable clinicians and pharmacists in the

practice of nutrition support and requires review of policies, protocols and procedures in order to

minimize errors or complications that may occur with PN therapy [20].

As a consequence of the intravenous (IV) delivery with PN, nutrients have a higher net rate as they

can be metabolized without any losses. This makes a parenteral prescription different from an

enteral.

Recommended nutritional composition of PN

-ESPGHAN/ESPEN *guidelines:

The newly published guidelines differentiates recommendations to the phase of illness :

- Acute phase = resuscitation phase when the patient requires vital organ support (sedation,

mechanical ventilation, vasopressors, fluid resuscitation).

-Stable phase = patient is stable on, or can be weaned, from this vital support .

-Recovery phase = patient who is mobilizing.

11

Table 2. Energy requirements for parenteral nutrition in different phases of disease [25]

Age (years)

Acute phase

(Kcal/kg/day)

Stable phase

(Kcal/kg/day)

Recovery phase

(Kcal/kg/day)

Preterm 45-55** 90-120

0-1 45-50 60-65 75-85

1-7 40-45 55-60 65-75

7-12 30-40 40-55 55-65

12-18 20-30 25-40 30-55

* ESPEN: European Society for Clinical Nutrition and Metabolism, ESPEN: European Society for Paediatric Gastroenterology Hepatology and Nutrition ** recommended energy intake during the first day of life.

2. Glucose* supply in infants and children according to body weight and phase of illness [26].

Weight

Acute phase (mg/kg/min, g/kg per day)

Stable phase (mg/kg/min, g/kg per day)

Recovery phase (mg/kg/min, g/kg per day)

28 days- 10 kg

2-4 (2.9-5.8) 4-6 (5.8-8.6) 6-10 (8.6-14)

11 - 30 kg

1.5-2.5 (2.9-3.6) 2-4 (2.8-5.8) 3-6 (4.3-8.6)

31 - 45 kg

1-1.5 (1.4-2.2) 1.5-3 (2.2-4.3) 3-4 (4.3-5.8)

> 45 kg

0.5-1 (0.7-1.4) 1-2(1.4–2.9) 2-3 (2.9-4.3)

*ESPGHAN/ESPEN guidelines are based on use of glucose solution (10%= 1 g= 4 kcal/ml)

3. Amino acid supply considered adequate for stable patients (g/kg/day) [27].

Preterm infants - First day of life - From day 2 onwards

1.5 - 2.5 2.5 - 3.5

Term infants* 1.5 – 3.0

2nd month to 3rd year* 1.0 - 2.5

3rd to 18th year* 1.0 – 2.0 * Critically ill patients may benefit from withholding parenteral nutrition while providing micronutrients during the first week of hospital admission.

4. Lipids [28]

- Intravenous lipid emulsions (ILEs) are an indispensable part of PN as non-carbohydrate source of energy delivered as an iso-osmolar solution in a low volume (2.0 kcal/ml with 20% ILEs, or 1.1 kcal/ml with 10% ILEs due to the higher relative content of glycerol)

- Generally a lipid intake of 25 to 50% of non-protein calories is recommended in fully parentally fed patients.

- In preterm and term infants, parenteral lipid intake should not exceed 4 g/kg/day

- In children, parenteral lipid intake should be limited to maximum of 3 g/kg/day

- Preference composite ILEs with or without fish oil (FO)

12

-ASPEN* guidelines [29, 30]

Table 3: According to ASPEN guidelines.

Age Preterm Term Infants

(0-1 yr)

1-3 yrs 4-6 yrs 7-10 yrs 11-18 yrs >18 yrs

Energy

(kcal/kg)

90-120 80-105 75-90 65-80 55-70 30-55 20-35

Dextrose* (GIR) (mg/kg/min)

Start=5-7 advance 1.4 - 1.7 mg Goal=10-14 (max 14-18)

Start= 6-8 advance 3.5 mg Goal=10-14 (max 14-18)

Start= 3-6 advance 2-3 mg Goal =8-10

Start= 3-6 advance 2-3 mg Goal=8-10

Start=3-6 advance 2-3 mg Goal=8-10

Start=2.5-3 advance 1-2 mg Goal=5-6

No > 5

Amino Acids (g/kg/day)

Start=1.5-3 advance by 1g/kg/d Goal=3-4

Start=1.5-3 advance by 1g/kg/d Goal= 2-3

Start=1-2 advance by 1g/kg/d Goal= 1.5-3



Start= 0.8-1.5 advance by 1g/kg/d Goal=0.8-2.5

Start= 0.8-2

Lipid (g/kg/day)

start= 1-2 advance by 0.5-1 g/kg/d Goal= 3-3.5 (max 0.17g/kg/hr)

start= 1-2 advance by 0.5-1 g/kg/d Goal= 3- 3.5 (max 0.15g/kg/hr)

start= 1-2 advance by 0.5-1 g/kg/d Goal= 2-3



start= 1 advance by 1 g/kg/d Goal= 1-2.5

No less than 1% total cal

OR

no >2.5 g/kg

*ASPEN: American Society for Parenteral and Enteral Nutrition, GIR: Glucose Infusion Rate. The ASPEN guidelines are based on use of dextrose solution (10% = 1 g = 3.4 kcal/kg).

Follow up

Application and duration of PN requires close calculation and monitoring, especially of the predictors

of complications. Some adverse events are frequently seen, such as sepsis, infections, muscle

weakness, oedema, osteoporosis, respiratory dysfunction, cardiac dysfunction and generally are

induced by metabolic disturbances, but can be avoided or minimized with appropriate prescribing

and monitoring. Moreover, hepatic dysfunction is a frequently seen complication in long term PN use

but this is more prevalent with the traditional soy-based emulsions such as Intralipid 20% ®[22, 31].

Table 4 summerizes complications of PN use.

13

- It is a multidisciplinary decision to start PN during KDT.

- Ensuring safe indications and compounding of PN solutions requires skilled and

specialised clinicians and pharmacists in both PN administration and calculation and in

KDT (enteral use).

- Start KD-PN in case > 48 hours enteral feeding is NOT possible.

- The administration of KD by parenteral administration should follow published guidelines

(ESPEN/ESPGHAN/ASPEN) and local policies where possible, except for the proportion

of carbohyrates, and lipids.

- In case the patient will start KDT initiated as PN: check for contra-indications of KDT

(i.e. congenital lipid metabolism disorders, carnitine deficiency)

- Use of KD PN in preterm infants should be avoided, if possible.

In acute conditions this might be different ( see Chapter 5).

Table 4. Summary of complications of PN use.

Complication

Glucose metabolism -Hypoglycemia

-Hyperglycemia

Fat metabolism -Hypertriglyceridemia

-Essential fatty acid deficiency

Protein metabolism -Hyperammonemia

-Metabolic acidosis

Micronutrients Deficiency of calcium, potassium, phospate, magnesium, zinc, selenium,

copper and fat- soluble vitamins.

Adapted from ESPGHAN/ESPEN guidelines [31]

In summary: application of PN in (critically) ill children is complex and TPN should be discouraged

during the acute phase of illness in children. In fact, special expertise is needed to keep a balance

between its risk and benefits, even when it is used for a short period of time. Its administration

during an intensive care unit (ICU) admission is challenging. This will be even more profound in case

PN is started in children already on a ketogenic diet or when children have to be initiated on a

ketogenic diet (i.e refractory status epilepticus, FIRES). The reason for this lies in the delicacy of the

changed metabolism essential for efficacy of this treatment, which requires intensive guidance of a

multidisciplinary team.

Based on the previous information the following recommendations are suggested by this group to

guide overall concepts for managing patients on PN, specific to the KDT:

RECOMMENDATIONS for starting KD-PN:

14

Chapter 4 Preparing for Parenteral Nutrition administration during

Ketogenic Diet Therapy. By Jessica Harvey

4.1 Medical history.

A thorough evaluation has to be completed by the child's neurologist, the multidisciplinary team, and

the ketogenic dietitian to determine if the ketogenic diet is the appropriate medical treatment. The

primary physician should rule out medical disorders that are contraindicated to the ketogenic diet,

including several metabolic disorders, severe liver function disorders and certain cardiovascular

diseases. This requires an accurate history, blood, and urine tests. The multidisciplinary team should

evaluate seizure history, growth, previous antiepileptic treatments, social data, and medical history.

4.2 Ketogenic Ratio.

If the child’s seizures have been effectively controlled on the KDT prior to initiation of KD-PN, the

goal would be to match the enteral ratio with KD-PN to maintain previous ketosis. However, due to

the ratio of fat to protein and carbohydrates combined and the addition of glycerin from lipids, a

ratio higher than a 2:1 may not be able to be attained. It should be investigated whether KD-PN is

needed to maintain current ketosis or obtain ketosis. If required to maintain the current state of

ketosis, it may be feasible to start with a lower ratio to provide more calories and protein, specifically

if the patient is malnourished or in a postoperative state. If the patient is in status epilepticus and

requires the ketogenic diet to break status, nutrition may be sacrificed to achieve a higher ratio.

4.3 Allergies.

Intravenous lipid emulsions have varying ingredients; therefore, it is important to discuss allergies

and hypersensitivities with the family prior to starting KD-PN. Intralipid ®20% are contraindicated in

hypersensitivity to egg, soyabean and peanut proteins. Olive-oil based IVLEs are contraindicated in

individuals with known hypersensitivity to egg, olive and soybean, peanut proteins, or to any active

ingredient, while multicomposite IVLE such as SMOF lipids ® should be avoided in patients who have

hypersensitivity to fish, egg, soybean, or peanut protein [32].

4.4 Medications.

Medications, including IV medications, should be converted to the lowest carbohydrate form.

Intravenous products are often mixed with dextrose or may provide calories, which could affect

ketosis negatively. Careful consideration needs to be taken when prescribing intravenous

medications. Collaboration with a pharmacist is needed to determine the total carbohydrate content

of medications prior to initiating treatment. For most patients, switching from liquid, enterally-

provided antiseizure drugs to tablets or IV preparations is advised.

15

4.5 Nutrition Status.

A thorough nutrition assessment must be completed prior to initiation of ketogenic parenteral

nutrition. Evaluation of anthropometric data should be completed including:

- weight and Z-core for weight for age on appropriate growth chart for gender, age and

diagnosis

- Height and Z-score for height for age on appropiate growth chart for gender, age and

diagnosis

- Weight and Z-score for weight for height for age on appropriate growth chart for gender, age

and diagnosis

- Z-score for BMI for age on appropriate growth chart for gender, age and diagnosis.

- Recent weight change

- Head circumference (until age of 2 years), Z-score for age.

- Growth velocity.

- Ideal body weight, percentage ideal body weight.

Note: if the patient is presented acutely, some of the above anthropometric measures may not be

available.

The Registered Dietitian must obtain and evaluate the patient’s nutrition history. The following

factors should be assessed:

- Analysis of recent intake, including evaluation of age-appropriate diet and caloric intake

- Method of feeding (oral vs enteral tube or both) and any swallow evaluations completed

- or scheduled. Chewing or swallowing ability, developmental ability or other feeding

difficulties

- Nutrition disorders with neurological impairments.

- Problems with bowel function such as diarrhea or constipation and bowel habits (i.e. altered

gastro intestinal (GI) function, impaired nutrient utilization).

- Factors affecting fluid requirements.

- Cultural preferences or restrictions.

- Use of vitamins/mineral supplements or nutritional supplements.

A nutrition focused physical exam can provide detailed information for the dietitian to determine

nutritional status by uncovering any signs of malnutrition, nutrient deficiencies, or nutrient toxicities.

In summary: however, in some situations, the urgency to stabilize the patients medical status

through the use of KD-PN may outweigh in the short term providing optimal nutrition for health. The

nutritional implications of both PN and KDT must be discussed with the patient’s medical team and

goals of PN and KDT at this critical time decided.

16


RECOMMENDATIONS for Ketogenic PN preparation.

DISCLOSURE PROOF OF PRINT VERSION DO NOT DISTRIBUTE!

- Evaluate the medical situation: confirm enteral administration of KDT (e.g

nasogastric tube feeding) is NOT possible.

- Clarify the indicator and expected longevity on the treatment.

- Evaluate the nutritional status: extra attention has to be made to malnourished

children.

- Be cautious with the use of lipid brands in case of allergies, check the nutritional

composition with the pharmacist.

- Change ALL medication to the lowest carbohydrate form possible.

17

Chapter 5. The Ketogenic Parenteral Nutrition prescription.

By Elles van der Louw, Vanessa Aldaz, Marian Roan and Stéphane Auvin.

5.1 Nutritional composition of Ketogenic PN.

In the critically ill patient special attention to the prescription of nutrients must be made. The

professional judgement of the attending health professionals is the primary component of quality

medical care administration and practitioners should always exercise their most professional judgment

and training when it comes to individual and case by case basis. Nutritional composition of KD-PN

should follow international guidelines for PN with adaptation for KDT and awareness of patients

nutritional needs.

5.1.1 Fluid.

In medical practice the total volume of PN is a factor limited by the volume required for dilution of the

wide range of medication that is utilised during ICU admission.

The fluids need varies and must be tailored to the patient's medical situation, body weight, excretion,

blood electrolytes, acid base status, haematocrit, urine-specific gravity and urine electrolytes [21].

The medical team determines the total volume available for PN prescription.

Guidelines

0-1 years

1-2 years

3-5 years

6-12 years

13-18 years

-ESPGHAN/ESPEN ml/kg/day [33]

120 - 150 (max 150-180)

80 - 120 (max 150)

80 - 100 60 - 80 50 - 70

-Maintenance fluids by Holliday-Segar formula [34]

1-10 kg 11-20kg >20 kg

100ml/kg 1000+50 ml/kg for each kg >10kg 1500ml +20 ml/kg for each kg >20kg

Literature

The following information has been found in the previous published cases of KD-PN:

- Roan M, 2011: average of 75% of enteral feeds fluids.

- Jung, D. et al 2012: n=10, 495 kcal/475ml as example, meaning average of 1ml/kcal.

- Lin, J. et al 2015: n=1, 1072ml/day for 7 years old child, 40 kg body weight.

- Farias-Moeller, F. et al 2017:

- 0-10 kg : 100ml/kg/day.

- 10-20 kg : 1000ml + 50ml/kg > 10 kg.

- 20-40 kg : 1500ml + 20ml/kg > 20 kg.

- > 40 kg : use adult recommendations

-Dressler,A. et al 2017: n=17, computer based algoritm is used to calculate the nutritional compo-

18

sition, fluid recommendation according ESPEN/ESPGHAN guidelines.

Expert opinion

There are no data from the survey on international expert teams concerning fluid calculation.


RECOMMENDATIONS for daily fluid requirement .

5.1.2 Energy.

The total energy needs are a sum of different components; basal metabolic rate (BMR), diet induced

thermogenesis, physical activity and growth. The energy needs must also be corrected for

malnutrition. Diet induced thermogenesis reflects the amount of energy needed for food digestion,

absorption and synthesis and is affected by the route of administration. In case of parenteral

administration this means a decrease of 10% of daily energy needs [25] .

The energy supply during ICU admission should be calculated based on Resting Energy Expenditure

(REE) measured with indirect caloric metry, which has to be tailored to the individual circumstances.

[21, 22, 25]. Repeated measurements should be obtained when medical situation of the patient

changes (e.g fever, inflammation, chronic disease). However, it is of importance to avoid

hyperalimentation because it may induce metabolic imbalances, liver damage and a serious refeeding

syndrome (particularly in severe malnourished patients)[21].

NOTE: if measuring REE is not feasible, equations should be used based on Schofield or WHO multiplied

by the appropriate activity and stress factor in case of parental administration [23, 25]. Table 5 shows

an overview of energy equations

- The medical team determines the fluid volume available for PN.

- Goal:

- 0-10 kg : 100ml/kg/day

- 10-20 kg : 1000ml + 50ml/kg > 10 kg

- 20-40 kg : 1500ml + 20ml/kg > 20 kg

- > 40 kg : use adult recommendations

- Minimal : 75% of calculated enteral fluids

Note: based on the clinical condition these goals may not be appropriate or possible.

19

Table 5. Overview of energy equations in kcal [35, 36].

Source Gender Equation

WHO 3-10 yrs

Male REE = 22.7 x Wt + 495

Female REE = 22.4 x Wt + 499

Schofield (Weight) Male BMR = 22.7 x Wt + 505

Female BMR = 20.3 x Wt + 486

Schofield (Weight/height) 3-10 yrs

Male BMR = 19.6 x Wt + 130.3 x Ht + 414.7

Female BMR = 16.97x Wt + 161.8 x Ht + 371.0 BMR: basal metabolic rate, REE: resting energy expenditure

Guidelines

-ESPGHAN/ESPEN [25]

The newly published guidelines differentiates recommendations to the phase of illness:

- Acute phase = resuscitation phase when the patient requires vital organ support (sedation,

mechanical ventilation, vasopressors, fluid resuscitation).

-Stable phase = patient is stable on, or can be weaned, from this vital support .

-Recovery phase = patient who is mobilizing.

-Calculated REE based on Schofield equation adding stress factors with caution to avoid

hyperalimentation. If available, measure REE with indirect caloric metry.

Age (years)

Acute phase

(kcal/kg/day)

Stable phase

(kcal/kg/day)

Recovery phase

(kcal/kg/day)

Preterm 45-55* 90-120

0-1 45-50 60-65 75-85

1-7 40-45 55-60 65-75

7-12 30-40 40-55 55-65

12-18 20-30 25-40 30-55

* recommended energy intake during the first day of life.

-ASPEN [23, 29, 30]

Age Preterm Term Infants (0-1 yr)


Calories (Kcal/kg/day)

90-120 80-105 75-90 65-80 55-70 30-55 20-35

- Measuring REE is first choice, in case this is not feasible then use Schofield or WHO equation

Add stress factors with caution as they might result in hyperalimentation.

-Target to reach at least 2/3 of caloric goal after one week.

20

Literature


-Roan, M. 2011: 50-75 % of calculated goal on calories that are mainly based on the volume that is

permitted with maximal fat content.

-Jung, D et al 2012: N=10 already on KDT: goal 50 % of estimated energy need. Mean duration of

TPN was short : 4.1 ( SD 1.5) days.

-Lin,J et al 2015: N=1, SRE on ICU, new onset of KDT: goal within 5 days 70 % of estimated energy

need.

-Farias-Moeller,F et al 2017: n=2/10 total PN for RSE: Caloric need based on only BMR for

intubated patients, BMR x 1.2-1.4 for extubated patients.

-Dressler, A et al 2017:, N=17. Calories are calculated based on ESPEN/ESPGHAN guidelines for fat

and protein intake and completed with carbohydrates; a median intake of 3 g fat/kg/day (27 kcal),

median intake of protein and carbohydrates of 3.66 g/day (14.6 kcal) results in median caloric intake

of 41 kcal/kg which is 50% of RDA.

Summary: aiming for 50% of calories as documented in some studies may be most feasible given the

low dextrose, protein and high fat content of the KD-PN prescription.

Expert opinion

Results from the survey of international expert teams show a high variety in the way energy need is calculated in clinical practice. Table 6A. How to calculate energy need (Survey opinion).

N=24 n

Metabolic chart/Indirect calorimetry

4

Range of 50-90% of RDA

5

RDA with stress factors

1

Age ranges: 1-7 y : 75-90 kcal/kg/day 7-12 y : 60-75 kcal/kg/day 12-18 y : 30-60 kcal/kg/day

1

Schofield equation 3

Dependent on PN prescription/volume

5

60-75% calories of enteral KD composition

2

Unknown

3

21

Table 6B. Calories at start (Survey opinion)

N=24 n

50-75% of calculated goal 14

< 50 % of calculated goal 2

Based on volume and composition PN 5

Unknown 3

In summary: in clinical practice it will be important to determine which goal to aim for as energy

need: the caloric intake that can be achieved based on a ketogenic diet composition might not

always be realized.

Based on this information the following recommendations were formulated:

RECOMMENDATIONS for energy requirement.

mendations for energy requirement.

5.2.3 Carbohydrates.

5.1.3 Carbohydrates

Prior to starting KD-PN it is of high importance to ensure all carbohydrates coming from oral or IV

fluids and medications are removed, as these extra carbohydrates can inhibit adequate ketosis and

efficacy of the therapy. It is also of high importance a pharmacist will calculate the carbohydrate and

alcohol content of all medication and sedatives/24 hours (see Table 7).

- Determine the ideal weight/age or weight/height to calculate the energy intake.

- Caloric need should be based on REE measurement and adding stress factors based on the

patients clinical situation. It is important to be aware of hyperalimentation.

Or, use Schofield equation (W/H), and add stress factors with caution to prevent

hyperalimentation.

- Start with 50% of calculated energy goal.

- Increase calories within one week to the maximum, with the aim of reaching at least the

BMR or 70-80 % of calculated energy requirement.

- When for short period of time (3-4 days) only 50% of calculated energy goal can be given,

this might be accepted.

Notice: monitoring ketones and glucose levels are of importance to detect hyperketosis

and/or hypoglycaemia as this might be exellerated by caloric restriction.

Restriction of calories to induce ketosis or achieve adequate ketosis must be discussed

and agreed with the patient’s medical team.

- Evaluate the caloric intake frequently and correct for changed medical situations

(e.g. fever).

22

Table 7. Carbohydrate and alcohol content of some intravenous products*.

Intravenous product Strength Carbohydrate/100ml Alcohol/100ml

Phenobarbital 130 mg/ml Glycerol 702 mg 79 mg

Diazepam 5 mg/ml Glycerol 414 mg 79 mg

Lorazepam 2 mg/ml Glycerol 753 mg -

Phenytoin 50 mg/ml Glycerol 414 mg 79 mg

Pentobarbital 50 mg/ml Glycerol 414 mg 79 mg

Famotidine 10 mg/ml Mannitol 20 mg -

Propofol** 10 mg/ml Glycerol 225 mg - * Note: it is important for clinical pharmacist to check composition of products used in their center.

** To be used with caution if possible to be avoided[37]

Most infusions on the ICU can be prepared in sodium chloride rather than in carbohydrates. Energy

from carbohydrate through use of dextrose provides 3.4 kilocalorie/gram, as glucose provides 4

kilocalorie/gram. Because most KD-PN preparations will be non-inclusive of dextrose or will contain

under 5% Dextrose, the glucose infusion rate will be very low to 0 mg/kg/min. If possible it would be

preferable to consider a 1-2.5% dextrose concentration as a maximum. In the case of fluid restriction

a higher % of dextrose might be required to establish an appropriate daily glucose administration.

However, some hospital inpatient pharmacies may not be able to formulate this properly given

mixing and compounding devices may require a small amount of dextrose and to ensure stability of

the solution.

There are limited published papers on the use of KD-PN; 3 articles used dextrose in their formulation

( [8-10]) and used a 5% dextrose and therefore cycled their PN for a shorter period of time (at 16 hrs

and off for 8 hours ) while cycling sodium chloride 0.45% in order to decrease total carbohydrate

allotment. This trend was most likely adapted from each other.

In order to maintain the level of ketosis during KD-PN, the daily carbohydrate intake of the regular

oral ketogenic diet should be used as benchmark for the maximum amount of carbohydrates coming

from the PN solution (for example; if the regular KD contains 25 grams of carbohydrates, use 25

grams as the maximum for the KD-PN prescription)

In clinical practice, the ultimate glucose intake depends on the diet ratio of the maximal possible lipid

intake and minimal protein intake that is needed to prevent for malnutrition but which also ensures

an adequate level of ketosis. Moreover, lLEs contain a range of 2.2-2.5% glycerol, which will also

deliver carbohydrates after metabolization.

See table 8 of most common IV lipid emulsions (internationally) and their glycerol content. The end

diet ratio will be different if this carbohydrate is considered.

TABLE 8 Glycerol content of some IV lipids.

Brandname IVLEs Glycerol content (%) Carbohydrate gram/100mL

SMOF® 20% 2.50 2.50

Intralipid ®20% 2.25 2.25

Nutrilipid ®20% 2.50 2.50

Lipofundin®* 20% 2.50 2.50

Clinolipid/Clinoleic® 20% 2.25 2.25

*contains 50% medium chain triglycerides.

23

Guidelines

There are no guidelines available or provided specifically for KD-PN.

- ESPGHAN/ESPEN [26]

- European guidelines are based on the use of glucose solution (10%=40 kcal/100ml).

- Glucose intake should cover 50% of non-protein calories, which is not aplicable in KDT.

- In critically ill children glucose intake should be limited; < 10 kg to 2-4 mg/kg/min and > 10 kg to

0.5-2.5 mg/kg/min advancing to goal < 10 kg to 6-10 mg/kg/min and > 10kg to 2-6 mg/kg/min.

- ASPEN [29, 30]

- American guidelines are based on the use of dextrose solution (10%=1 g=3.4 kcal/ml).

- Addition of dextrose:

GIR is recommended at 3-6mg/kg/min and advancing by 2-3 mg/kg/min to a final goal of 8-10

mg/kg/min for children 1-10 yrs. In adolescents these recommendations are lower starting at

2.5-3 mg/kg/min and advancing by 1-2 mg/kg/min with a goal of no more than 5-6 mg/kg/min.

Preterm and term infants have higher tolerance levels.

- In general, dextrose content should not exceed glucose oxidation or glucose infusion rate as it

results in fat production and in some cases it has been associated with hepatic steatosis. Glucose

excess above the oxidative capacity should be avoided in long term PN patients as it may increase

the risk for intestinal failure associated liver disease (IFALD).

-Glucose intake should cover 40-60% of total caloric intake, which is not applicable in KDT.

-Other specific guidelines provided by ASPEN for those children with insulin dependence

(type 1 DM).

- White paper [38]

-PN may be cycled over 12 hours to limit the dextrose intake, while providing dextrose free fluids

during the remaining hours.

-The glycerol content from the lipid emulsion will provide minimum requirements to preserve

glycolysis.

Literature


-Roan, M 2011: Use NO dextrose, if blood glucose < 50 mg/dl than add dextrose 2.5 % or 5% to PN.

-Jung, D et al 2012: N=10 already on KD: 4:1 diet ratio containing 7.5 g protein/500 kcal/5 gram carbs

as 50% of regular 1000 caloric 4:1 KD, is cycled given.

-Lin,J et al 2015; N=1, SRE on ICU, new onset of KD: first 2 days 0% dextrose, from day 3 use of 5%

dextrose to 16.5 gram carbs/day depending on ketone levels and is cycled given.

-Farias-Moeller,R et al 2017: n=2/10 total TPN for RSE: dextrose free solution.

-Dressler,A et al, 2017: Median intake glucose 1.7 g/kg/day (IQR 1.5-2.4) in range 0.5-3 g/kg/day .

Expert opinion

From 24 centers, 58% do not calculate glycerol as part of the carbohydrate content in the diet ratio.

Around 46 % of the centers at start use a dextrose-free solution compared to 42 % of the centers

who start with a low glucose intake.

24

Table 9. Calculation of carbohydrates (Survey opinion)

N=24 n

0% dextrose solution 11

Glucose 2.5% 2

Depending on diet ratio 2

Depending on carbohydratecontent regular KD 3

Glucose 1-2 % 2

75-350 mg/L 1

Unknown 3


RECOMMENDATIONS for carbohydrate requirement.

5.1.4 Protein.

Parenteral nutrition amino acid administration results in an average of 17% lower available amount

of protein; a protein need of 0.8 grams/kg requires a 1.0 gram intake of aminoacids from TPN [27,

39].

In addition, the protein requirement is increased by as much as 20%-50% in critical illness, thermal

injury and catch-up growth [29]. Critically ill patients are at risk malnutrition principally as a result of

protein breakdown that is directly related to the seriousness of their condition. An intake of 1.5 g

protein/kg/day is adviced as the minimum to prevent for malnutrition [23, 27].

Protein is delivered as a crystalline amino acid solution which provides 4 kilocalorie/gram. It is

important to notice that pediatric amino acid solutions are manufactured with increased

concentrations of Histidine and Tyrosine and low concentrations of Phenylalanine, Methionine and

Glycine. They also contain Glutamic acid, Aspartic acid and Taurine which are typically not included in

standard amino acid products. The pediatric amino acid solution is also lower in PH, which allows

higher amounts of calcium and phosphorus to be included [29]. Infants and young children should

receive pediatric amino acid solutions with adequate amounts of Cysteine, Taurine and Tyrosine

because they are conditionally essential during illness [27].

- Limit carbohydrate intake from oral or IV fluids, medication and sedatives to the maximum.

- Be aware of the carbohydrate content from glycerol of the maximum lipid prescription and

medication as this interferes with the diet ratio (table 8).

- If the clinical situation allows ( acute illness, current ketone and blood glucose levels), a 0%

dextrose/glucose composition could be used at start as some carbohydrates will be delivered by

glycerol metabolization.

Dextrose/glucose should be increased step by step based on blood glucose and ketones, age and

condition of the patient.

Try to aim for the maximum grams of carbohydrates of the regular, enteral KD prescription.

In case this is not possible; the lowest glucose % available should be used and run for 12 hours

with Sodium Chloride 0.45% for remaining hours.

- In general; give PN continuously, only in case of long term use run it in cycles to prevent

complications.

25

During KDT, protein and carbohydrates are as non-ketone producing nutrients part of the dietratio.

To ensure an adequate intake of protein, essential for growth, the intake of carbohydrates might be

sacrified for optimal diet efficacy. During KDT it is recommended the protein intake follows the

recommended daily allowances of ideal weight for age, with special attention to infants [40, 41]. In

KDT literature, the study of Nation et al, 2014 reports in a cohort of 35 children during KDT a

protein/energy a ratio of < 1.4 g protein/100 kcal was associated with poor linear growth while a

ratio of > 1.6 g was associated with adequate linear growth. A ratio of 1.5 g protein/100 kcal can

indicate the ‘‘cut off’’ ratio between the two trends [42].

Guidelines

-ESPGHAN/ESPEN [27]* (amino acids g/kg/day)

Preterm infants - First day of life - From day 2 onwards

Term infants

2nd month to 3rd year

3rd to 18th year*

1.5 - 2.5 2.5 - 3.5

1.5 – 3.0 2.5 2.0

- White paper [38] (g/kg/day)

1.5 during stress 0.5-0.8 for short term use might be accepted

*Critically ill patients may benefit from witholding PN while providing micronutrients during the first week of hospital admission.

- ASPEN [29, 30]



Amino Acids (g/kg/day)

3-4 2-3 1-3 1-3 1-3 0.8-2.5 0.8-2

In summary: international guidelines recommend 1.5 gram/protein/kg is needed to prevent for

malnutrition. However, a higher intake might be needed depending on the medical situation and

nutritional status of the individual child.

Literature

The following information has been found in the previous published cases of KD-PN on protein:

-Roan, M 2011: 1 g/kg /day, but 0.5-0.8 g is more realistic concerning diet ratio.

-Jung, D et al 2012: N=10 already on KD: units carb/protein calulated of 4:1 ratio. Not clear how

much protein/kg.

-Lin,J et al 2015: N=1, SRE on ICU, new onset of KD: 16.5 g protein/day calculation based on 40 kg

makes 0.4 g/kg .

-Farias-Moeller,F et al 2017: n=2/10 total PN for RSE: no information on protein intake.

-Dressler, A. 2017: N=17, median 2 g/kg/day (IQR = 1.5–1.5; range 1.5– 2), very young children

(median age 1.8 years)

Expert opinion

26

Results from the survey show 63% of the expert centers calculates > 1 g/kg into the TPN prescription.

It is unclear whether they are able to reach the minimal amount of 1.5 g/100 kcal to prevent

malnutrition.

Table 10. Calculation of proteins (Survey opinion).

N=24 n

0.5 g/kg or less 4

0.6 - 1 g /kg 5

1.1 - 2 g/kg 8

> 2 g/kg 7

In summary: during KD-PN, optimizing the diet ratio to the maximum, limits the intake of adequate

protein and carbohydrates. Therefore, in clinical practice priority is given to protein intake to prevent

malnutrition and by the general omission of carbohydrates (when the glucose and ketone levels

allow this). Aim for the optimal protein intake and check if the minimal intake (1.5 g/100 kcal or 1.5

g/kg/day) is met.


RECOMMENDATIONS for protein requirement.

5.2.5 Lipids/diet ratio.

5.1.5 Lipids/diet ratio.

Lipids are an important component of PN as they highly contribute to the caloric intake in a low

volume and low osmolarity so are suitable for peripheral infusion. They also provide essential fatty

acids. A minimal intake of 0.25 g/kg/day in infants and 0.1 g/kg/day in older children should prevent

for essential fatty acid deficiency [28]. In KD-PN the delivery of lipids is of utmost importance to

ensure the level of ketosis is reached that is needed for seizure control. In clinical practice this is

challenging. In KD-PN 10% solutions of ILVE should be avoided.

- Determine ideal weight/age or weight/height to calculate the protein intake.

- Aim for minimal 1.5 g/kg for youngest children, 1 g/kg for older children, OR use

1.5 g /100 kcal/day.

- Minimum 0.5 - 0.8 g /kg for short term use might be acceptable to benefit ketosis.

- Be aware of conditionally essential amino acids.

- Careful professional judgement of proposed recommendations must be taken into

consideration of each individual circumstance.

For example, those that are in critical condition may need higher protein

prescriptions than recommended in healthy children, depending on renal

function.

During catabolic states such as post-surgery or chronic or acute illness, more

protein might be required to promote positive nitrogen balance.

27

Guidelines

Infants Children

-ESPGHAN/ESPEN [21, 28] (Lipids, g/kg/day)

Start with 2 Advance by 0.5-1 Goal 4

Start with 2 Advance by with 0.5-1 Goal 3

- White paper [38] (Lipids, g/kg/day)

Start with 2-3 Goal 4

- ASPEN [29, 30]



Lipids g/kg/day

3-3 .5 3-3.5 2-3 2-3 2-3 1-2.5 No less than 1% total cal, OR No >2.5 g/kg

-Start with 0.5-1 g/kg/day and advance by 0.5-1 g/kg/day with a goals of 3.5 g/kg/day max

0.15g/kg/hour for preterm and term infants.

Start with 1-2 g/kg/day in children 1-10 yrs and advance by 0.5-1 with a goal of 2-3/kg/day.

For adolescents: start with 1 g/kg/day and advance by 1 g/kg/day with a goal of 1-2.5 g/kg/day.

In general (ESPGHAN/ESPEN/ASPEN guidelines): a continuous infusion is better tolerated. Daily

maximum is 50-60% of energy.

-White paper [38]: run lipids for 24 hours to improve tolerance. A 4:1 diet ratio might not

be achieved depending on maximum of lipids tolerated and the accompanied amount of glycerol

but still effective to reduce seizures.

Literature


-Roan, M 2011: max of 4 g/kg , run less than 0.15-0.25 /g/kg/hour.

Omegaven ® or IV MCT oil preparations; not approved by the Federal Drug Administration (FDA) in the US but available in Europe but not recommended by ESPHGAN/ESPEN. -Jung, D et al 2012: N=10 already on KDT: units calculated based on 4:1 diet. 4.1–4.5 g/kg/day (50 g

fat per 1,000 kcal), 20% lipid solution is used.

-Lin,J et al 2015: N=1, SRE on ICU, new onset of KDT: 20% SMOF lipids used, build up in 5 days up

to > 3 g/kg/day.

SMOF Lipid® infusions preparations; not yet FDA approved in the USA but available in Europe. -Farias-Moeller,F. et al 2017: n=2/10 total PN for RSE: 3:1 and 2.75:1 diet was calculated but no

information on g/fat/kg.

-Dressler, A et al 2017: N=17, the lipid intake was median 3 g/kg/day (IQR = 3–3; range 3–4) and

28

diet ratio 0.9:1 (SD = 0.28; range 0.6–1.5). Intralipid was used in 29% (5/17), Clinoleic in 41%

(7/17), and SMOF Lipid® 20% in 29% (5/17). Expert opinion Results from the survey show most centers start with 1-3 g/kg, increasing with steps of 1-1.9 g/kg up

to goal 3-4 g/kg/day. Most centers run PN lipids continuously.

Table 11. Calculation of lipids (Survey opinion)

N=24 n

How do you start your lipids? 50% of goal 1 g/kg 2 g/kg 3 g/kg Start with goal Other

6 7 5 1 0 5

What is your goal for lipids? ESPGHAN/ASPEN guidelines : 3-4 g/kg Other Unknown

4 17 2 1

How long do you run your lipids in 24 hours?

24 hours 20 hours Intermittent

17 3 4

How do you advance your lipids to goal?

1 - 1.9 g/kg/day 2 - 4 g/kg/day Already started with goal Other Unknown

13 2 2 6 1


RECOMMENDATIONS for lipid requirement and application.

- Start with 2 g/kg/day for Europe of SMOF Lipids ® 20% and if available in USA otherwise use

Intralipid ® 20 Liposyn I-III ® 20-30%.

- Advance the lipids to goal, with steps of 1-2 g/kg/day.

- Goal is to reach 3 g/kg/day, up to max 4 g/kg/day, depending on tolerance and ketosis.

- Run PN lipids for 24 hours.

- Diet ratio (glycerol included (see above): aim for the maximal possible.

Try to increase the ratio in case of unstable ketone levels by reducing or stopping the glucose

infusion if required.

- Consider carnitine (50mg/day-max 1000mg/day) to stimulate fatty oxidation. Carnitine

supplementation may be considered in children expected to receive PN for more than 4 weeks

on an individual basis.

29

5.1.6 Vitamins/minerals.

Parenteral vitamins are usually applied as a mixture of different vitamins. Vitamins pose particular

pharmacological problems, when given intravenously, since some may adhere to the tube and/or be

degraded by light. Also stability in regard to admixture and ‘‘ingredients’’ may have an effect [43-45].

Therefore, the actual amount of vitamins delivered to the patient may be lower than the

intended dose. Little new data has been published in this area over the last 20 years. Therefore, it is

not possible to give fully evidence based recommendations.

Guidelines

Vitamin/mineral Infants (dose /kg/day)

Children (dose/day)

-ESGPHAN/ESPEN [43-45]

Lipid soluble -Vit A (μg) -Vit D (μg) -Vit E (μg) -Vit K (μg) Water soluble -Vit C (mg) -Vit B1 (mg) -Vit B2(mg) -Vit B6(mg) -niacin(Mg) -Biotine(μg) -Folic acid (μg) -Vit B12 (μg) -Pathotenic acid (mg) -Iron (mg) -Copper (μg) -Iodin (μg) -Manganese (μg) -Molybdeen (μg) -Selenium (μg) -Zink (μg) -Calcium (mg/kg) -Phosphorus (mg/kg) -Magnesium (mg)

150-300 40-155 IE 2.8-3.5 (<11 μg) 10 15-25 0.35-0.50 0.15-0.20 0.15-0.20 4.0-6.8 5.0-8.0 56 0.3 2.5 5 20 1 1 0.25 2-3 250 < 3mo 100 > 3mo 20-60 15-40 2.4-5

150 400-600 IE <11 μg 200 80 1.2 1.4 1 17 20 140 1 5 5 < 0.5 mg 1 1 0.25 < 100 50 10-16 6-22 2.4

- ASPEN[30] Lipid soluble -Vit A (μg) -Vit D (μg) -Vit E (μg) -Vit K (μg) Water soluble -Vit C (mg) -Vit B1 (mg) -Vit B2(mg) -Vit B6(mg) -niacin(mg) -Biotine(μg) -Folic acid (μg) -Vit B12 (μg) -Panthotenic acid (mg)

700 (retinol eq.) 10 7 mg 200 Water soluble 80 1.2 1.4 1 17 20 140 1 5

700 (retinol eq.) 10 7 mg 200 Water soluble 80 1.2 1.4 1 17 20 140 1 5

30

-Iron (μg) -Copper (μg) -Iodin (μg) -Manganese (μg) -Molybdeen (μg) -Selenium (μg) -Zink (mcgr) -Calcium (mg/kg) -Phosphorus(mg/kg) -Magnesium (mg)

Based on labs 20 1 1 n/a 2 50-250 0.5-4 0.5 to 2 0.3-0.5

Based on labs 5-20 Not well defined 1 Not routinely added Selenium: 1-2 50-125 mcg/kg > 40 kg 2-5 mg/d 10-20 10-40 10-30

-White paper [38]

No specific recommendations mentioned.

Literature The following information has been found in the previous published cases of KD PN:

- Roan, M. 2011: use standard multivitamins and multi-electrolytes, start 2-25 mcgr Selenium/kg/day

as deficiency could occur. In case of longterm use PN it is recommended to add 1 mg vitamin K/day

and in the case of diarrhea to ad Zinc (10-15 mg per L of output)[46].

- Jung,D et al 2012: no information on kind and vitamin and mineral supplementation.

- Chiusolo, F. et al 2016 : vitamin and mineral supplementation based on ESPEN/ESPGHAN guidelines

2005.

- Dressler, A et al 2017: ESPEN/ESPGHAN guidelines for vitamins, minerals and trace elements are

calculated with computer based algoritm.

Use of Soluvit, Vitalipid, Peditrace, Calcium gluconate, Potassium, Sodium , Glucose 1 phosphate

and Magnesium gluconate.

Expert opinion

Results from the survey shows the majority of the centers add multivitamins to TPN.

Table 12. Suppletion of vitamins (Survey opinion).

N 24 n

Add a multivitamin Yes 20

Sometimes 3

Sometimes, depending on duration PN 1

31

Based on the previous information the following recommendations were formulated.

RECOMMENDATIONS on vitamin and mineral suppletion


5.2 Initiation.

Guidelines

- ESPGHAN/ESPEN [20, 21]:

-TPN should only be started and monitored with multidisciplinary nutrition support team guidance.

- Time to start TPN depends on individual circumstances; infants may have to start immediately as

older children longer periods (up to 7 days) may be tolerated.

-At start a nutritional assessment should be done with aim to establish baseline subjective and

objective nutritional parameters to judge the effects of parental nutrition, and is divided into

clinical examination, anthropometry, laboratory indices, and assessment of dietary intake[47].

It should also identify specific nutritional deficits, determine nutritional risk factors for individual

patients, establish nutritional needs, and identify medical and psychosocial factors influencing

the prescription and administration of parenteral nutrition.

- ASPEN [23]:

-Timing when to start PN should be individually based on the nutrition and clinical status of the

child but not earlier than after 2 days of NPO.

- No information is given on how to build up the PN.

- White paper [38]:

-No recommendations on timing of PN initation.

- Lipids start at 2-3 grams/kg /day and build up 0.5 grams/kg/day to maximum of 4 grams/kg/day

and be given continuously (24 hours).

- protein intake 1.5 gram /kg/day idealy and 0.5-0.8 gram/kg/day is realistic during KD treatment but

no information given how to start.

- Amount of carbohydrates used differences between institutions but should be given during 12-16

hours and no information is given how to build up.

-Diet ratio can be lower than KDT by enteral route and in the range of 1.0:1 - 2.0:1[6, 8, 10].

- Add multivitamins based on RDA for age and/or weight to PN and follow doses per

manufacturers recommendations as content may slightly differ. Follow international guidelines

for supplementation.

- Check for Selenium and vit K deficiency in long term use of PN.

- Check for Zinc deficiency in case of diarrhea, 10-15 mg Zinc per L of output (diarrhoeal

or fistula output) in case of deficiency.

- Use organic Phosphate preparations to avoid interference with other ingredients of PN.

- Should KD-PN be only for 48-72 hours, extra vitamin supplementation may not be fully required

32

Literature

Information on KD PN initiation in literature is summarized in table 13.

Table 13: Overview of ways of Ketogenic PN initiation in literature. Study Population Way of initiation Notes

Rosenthal E, et al (1990) Case report [6]

5 years old patient refractory epilepsy and intractable diarrhea.

-no information on initiation -after switch to PN with 70% MCT/30% moderate ketosis was reached.

- already on KDT - diet ratio PN: 4:1 - duration PN unknown

Jung, D.E et al, (2012) Retrospective Study [8]

N=10 Children (age 1,1 -11.7 years old, 7 boys and 3 girls) with intractable epilepsy

-no information on initiation -7.5 g protein/1000 kcal 50 g fat/1000 kcal 5 g carbs/1000 kcal Ketone levels: no information

-new on KDT -n=8 on 4:1 PN diet ratio -n=2 on 3:1 PN diet ratio based on 50% of estimated energy need.

Strzelczyk, A. et al (2013) Case report [9]

21 years old patient with SRSE

1. 1000 kcal for first 24 hours 1566 kcal the days after 2. 15 grams protein and 10 grams carbs first 24 hours 3. 22.5 grams protein and 15 grams of carbs the days after ketone levels 1+ urine after 3.5 days and 4+ urine from day 4 onwards.

- new on KDT - diet ratio 4:1 - MCT fat used - PN given in 16 hours - total duration 27 days

Lin, J.J et al (2015) Case report [10]

6 years old child with SRSE

day 1-2: 1/3 of 70% energy need, aminoacid 4% (11 gram/day) NO carbs, 440 kcal/day day 3-4: 2/3 of 70% energy need, aminoacid 4% (11 gram/day) dextrose 5% (11 gram/day 880 kcal/day day 5 3/3 of 70% energy need, and on: aminoacid 4% ( 16.5 gram/day) dextrose 5% (16.5 gram/ day) Ketones > 2mmol/l blood in 96 hours.

- new on KDT - diet ratio 4:1 - PN given in 16 hours - total duration KD TPN: 5 days.

Chiusolo, F. et al (2016) Single case in retrospective review [11]

1/47 8 years old boy with SRE

PN was build up in 3 days 1. 0.45 g prot/kg 1.85 g fat/kg 0.45 g carbs, Ratio 2:1 2. 0.45 g prot/kg 2.0 g fat/kg 0.45 g carbs Ratio 2.2:1 3. 0.45 g prot/kg 2.4:1 g fat/g 0.45 g carbs Ratio 2.4:1 Ketone levels after 3 days full TPN: 2.6 mmol/l BHB

- new on KDT - PN was given continuously - duration full TPN was 3 days

33

Appavu, B. et al (2016) Single case as part of a retrospective review [12]

1/10 5 years old patient with SRE and intractable diarrea

- started with 50% of estimated energy need and increased for 10% every day anesthesia was tapered. - no information on how the PN was initiated/build up. - 13 days until ketonuria

- new on KDT - diet ratio 4:1 - run in 20 hours - duration PN 9 days

Farias-Moeller ,R. et al (2017)2 cases as part of a retrospective study [13]

2/9 (both 5 years) -no information on diet initiation. -3+ urine ketones within 4 and 5 days

- new on KDT - diet ratio PN 3:1 and 2.75:1 - duration KD 0.25 and 0.5 month

Dressler, A et al (2017) Prospective observational study [14]

(N=17) (median age 1.8 years)

Computer based algoritm to calculate the KDT. 50% of daily energy need, started immediately, enteral feedings as soon as possible.

-13/17 already on KDT -median duration PN was 3 days. - meandietratio was 0.91:1

Expert opinion

-Lipids: centers start 50% of goal lipids or build up 1-2 grams lipids/kg/day up to 3-4 grams lipids/day

maximum.

- Protein: no information on protein intake at start nor how to build up.

- Glucose: most centers use NO glucose OR use the amount of carbohydrates of the enteral KD of

the child.

- Diet ratio: is build up to maximal range between 2.0:1-3.0:1.

- Ketosis: 58% of centers were able to reach or maintain ketosis while on PN.

- Energy: most centers have their own protocol of building up energy to goal.

In summary: based on evidence and clinical practice it is clear that during KD-PN a certain level of

ketosis can be reached within a few days time. There are several ways of initiation possible and it is

not clear which way is most effective. The KD-PN must be started when a child is expected to be nil

by mouth for more than 48 hours, but must be based on the individual medical situation and has to

be tailored to a stepwise introduction which leads to a composition with the highest diet ratio as

possible with the lowest complications.

Notice: appendix II shows calculated examples illustrate several ways of KD-PN initiation and administration.

Paragraph 5.1 and 5.2 are summarized in the following recommendations for Ketogenic PN calculation and initiation.

34

SUMMARY of consensus recommendations for Ketogenic PN calculation and initiation.

- Nutritional composition of KD-PN should follow international guidelines ESPGHAN/ESPEN/

ASPEN for PN with adaptation for KDT and awareness of patients nutritional needs.

- Start parenteral administration of KDT exclusively in the case NPO of > 48 hours is

expected.

- Check for contra-indications in case of newly start KDT.

- Careful evaluate the medical and nutritional status: preterm infants and malnutrished

children are at risk for complications and therefore PN should be omitted.

- Change all medication to non-carbohydrate form if possible (pill, tablet or pharmacy

compounded). Notice the carbohydrate and alcohol content of the intravenous product

should be calculated into the final KD-PN diet ratio.

- Additional fasting can be performed at KDT initiation for the maximum of 24 hours to benefit

ketosis in case of newly start KDT.

- Obtain baseline nutritional assessment: use ideal weight/height and height.

If available: measure REE and RQ. Notice the risk for hyperalimentation.

- Fluid: determine the net fluid volume available for PN. Notice the medical situation, body

weight, excretion, blood electrolytes, acid base status, haematocrit, urine-specific gravity and

urine electrolytes of the patient.

- Calories: start with 50% of goal and build this up within max of 1 week when lipids are

increased, aim for BMR or 70-80 % of calculated energy requirement .

Intake of 50% of calculated energy goal might be accepted for limited period (3-4 days).

Notice: hyperketosis and/or hypoglycaemia might be accellerated by caloric restriction.

- The use of glucose /dextrose might be avoided for 3-4 days at KD-PN initiation to benefit

ketosis, when this is clinically appropriate. Administer sodium chloride 0.45% or other fluids

appropriate based on electrolyte need.

Subsequently; based on ketone and glucose levels and laboratory checks: use the lowest

dextrose % available OR start dextrose 5% solution delivering the amount of carbohydrates of

the original enteral KD as the maximum.

- Protein: start with full protein as goal, aim for minimal 1.5 g /kg/day but 0.5-0.8 g/kg/day

may be accepted temporally to benefit ketosis.

- Lipids: start with 50% of goal of lipids OR 1-2 grams/kg day. Build up lipids every 1-2 days

(based on TG level) to maximum of 4 grams/kg/day. Run lipids continuesly. Notice possible

allergy or hypersensitivity of the patient to fish, egg, soybean, or peanut protein.

- Diet ratio: start with 1:1 ratio and build up every 1-2 days to as high a ratio as possible.

Aim for a diet ratio within range 2.0:1-2.9:1 (incl glycerol from lipid emulsion) within 3-4 days.

Aim for the highes diet ratio possible with the lowest complications.

Consider carnitine supplementation (50-1000 mg/day) to benefit ketosis.

- Delayed treatment (after 7 days) might not be an option under KDT (to maintain ketosis) or

require a KDT urgently (to reach ketosis) for epilepsy treatment (i.e. RSE, FIRES)

- Vitamins/mineral suppletion should be appropriate for age and/or weight of the patient.

- Appropriate level of ketosis might not always be established; in case epilepsy improves this

might be accepted.

Application of these Ketogenic parenteral recommendations in medical practice have to be

tailored to the medical protocol of each individual expert center.

We strongly recommend that centers implementing KDT parenterally have experience in

enteral use of the KDT as well.

35

Chapter 6 Treatment phase. By Elles van der Louw and Dorine van den Hurk.

6.1 General.

The survey on 24 international expert teams from nine countries contains information on how the diet

is used in clinical practice on initiation, complications and monitoring.

The scientific evidence as reported in this chapter is mainly based on casereports, one retrospective

study an there are no prospective trials.

International guidelines (ESGPHAN/ESPEN and ASPEN) have recently been evaluated and this

information on diet initiation, adverse effects and monitoring gives guidance to the PN in pediatric

patients but to be evaluated from the KDT prospective.

6.2 Adverse events.

6.2.1 Adverse events due to parenteral nutrition.

Guidelines

-ESPGHAN/ESPEN [31]:

There are five groups of complications:

1. Complications of central Venous Catheters (CVC):

The most important CV complication is CVC related sepsis. Strict CVC handling, use of aseptic locks

such as taurolidine reduces the risk of CVC related sepsis. Amino acids and glucose sets and

extensions should be changed every 72 hours and lipid sets every 24 hours. Especially those patients

with severe malnutrition are at risk.

2. Complications related to the PN composition :

-Stability: the use of organic bound phosphates reduces the risk of precipitation. A licenced

manufacturer is advised to prepare the admixture formulation to ensure the formulation is

chemically stable. The formulation would be unlikely to be compatible with other medication so

would need to be administered separately.

-Drug compatibility: steroid related hyperglycemia or hypoglycemia is most common with concurrent

insulin. Monitoring of other concurrent therapy is important to allow appropriate and safe

prescription of the TPN. For example, hypokalemia is a common side effect of loop diuretics and may

require an adjustment of the prescription.

3. Mechanical events:

Mechanical events such as occlusion, leakage and dislodgement are commonly seen. Catheter

occulsions might be caused by PN components like lipids and calcium/phosphorus or by thrombosis.

Recognition of the probable cause is critical to appropriate intervention and salvage of the catheter.

4. Metabolic complications:

-Metabolic bone disease: decrease bone mineral density, osteoporosis, pain and fractures are

described as complications of longterm TPN use in adults and little data of children exists.[48]. During

TPN it is important to check calcium, vitamin D , phosphorus, and PTH.

-Hepatobiliary complications: during TPN hepatobiliary complications as cholestasis and steatosis are

frequently seen. Early and frequent monitoring of liver panel (ASAT, ALA, billirubin) is recommended.

36

5. Growth retardation

Studies in children on long-term parenteral nutrition have reported high prevalence of growth

deficits and abnormal body composition. Since abnormalities in body composition may

have long-term metabolic consequences, growth and body composition monitoring are important

parameters to investigate and monitor in these children [49]. Hence KD-PN is not a long term option

this complication does not concern this topic.

- ASPEN [23, 29, 30]

The recently updated guidelines contain no information on complications and monitoring TPN.

Information from manuals [29]: initiation of enteral nutrition as soon as medically appropriate is the

Key to minimizing potential adverse effects of TPN.

Complications can be “mechanical” meaning issues with infusion devices or TPN bags, administration

sets, catheters leaking or breaking or catherter tip migration (pheumothorax).

Complications can also be infectious (CLABSIs), metabolic such as hyperglycemia, hyper-

triglyceridemia, fluid and electrolyte imbalances, acid-base disorders, IFALD, metabolic bone disease,

refeeding syndrome, essential fatty acid deficiency (EFAD), nutritional (micronutrient and/or trace

element deficiencies or toxicity such as iron deficiency or aluminum toxicity.

6.2.2 Adverse events due to Ketogenic Parenteral Nutrition.

The available guidelines include complications in general PN use but provide no specific information

when used during KDT.

When the KDT is established as PN treatment for SRE/FIRES, adverse effects that are known during

KDT initiation might occur (i.e. hypoglycaemia, constipation) [1]. This highlights that close monitoring

is of high importance especially to avoid hypoglycemia, hyperketosis and/or hyperlipedemia.

- White paper[38].

Side effects of KD-PN include transient elevated triglycerides, cholesterol, liver function tests and

pancreatic enzymes which have to be closely monitored.

Literature

Reported complications of PN use during KDT are summarized in table 14.

37

Table 14. Reported complications of Ketogenic PN in children .

Study Population Complications


5 year old patient with intractable diarrhea. KD PN with MCT fat was used

abnormal liver function , severe iron deficiency of unknown etiology, serum triglycerides and cholesterol increased to 1717mg/dl and 614 mg/ dl

Roan, M. (2011) Case report [7]

18 year old patient with gut failure. KD PN x 14 mo with intralipid + EN trophic 3:1 feeds at 1 kcal/mL

No lab abnormalities found except drop in prealbumin to 15 mg/dL (normal range 17-34 mg/dL) during acute illness and returned to normal range with recovery.

Jung, D.E et al,

(2012)

Retrospective study [8]

10 children Age range 1.1-11.7 years, 7 boys/3 girls

Mean duration PN 4.1 days 10/10 (100%): hypertriglyceridemia (< 1000 mg /dl) 1/10 (10%): elevated amylase and lipase, abdominal pain. 1/10 (10%): aspartate aminotransferate and/or alanine aminotransferase.


21 year old patient with SRSE

No complications were seen during 27 days of PN

Lin, J.J et al (2015) Case report [10]

6 year old child with SRE

increased triglyceride/cholesterol values. amylase and lipase values were transiently elevated without clinical signs.

Chiusolo, F. et al (2016) Single case as part of a retrospective review [11]

1/47 8 year old boy with SRE

During 3 days of KD-PN levels of lipids, liver function parameters , amylase and lipase increased above normal ranged but remained so during enteral KD.



no specific complications of IV KD mentioned.

Farias-Moeller ,R. et

al (2017)

2 cases as part of a retrospective study [13]

2/9 children with SRE (both 5 y)

Both (100%) showed hypertriglyceridemia One (50%) showed pancreatitis (based on Valproate use)

Dressler, A et al (2017) Prospective study [14]

17 infants with epilepsy

During total PN no adverse effects. 1/17 during 41 days total PN mild disturbance of lab controls (cholesterol 164, triglycerides 113, HDL 33, LDL 108, VLDL 23, GGT 17, GOT 28, GPT 25, and LDH 224).

Baumeister, F.A. (2004) [50]

10 year old boy with catastrophic epilepsy started KDT as PN during propofol anasthesia.

Propofol, containing 10 % triglycerides, contributed 20 % of the daily lipid supply (6.8 g/kg/d) resulted in cardiac problems hyperlipidemia (serum triglycerides 5200 mg/dl; serum cholesterol 440 mg/l), rhabdomyolysis (maximum of serum creatinine phosphokinase [CK] 18 900 U/l, CK-MB isoenzyme 700 U/l, pigmenturia), and metabolic acidosis with a lactate of 6.4 mmol/l and death.

38

Expert opinion The survey on 24 international expert teams from 8 countries and report complications of KD PN are

summarized in table 15.

Table 15. Summary of complications seen by KDT centers during Ketogenic PN use

(Survey opinion).

Complication Incidence

Hyperlipidemia

17/24

Insufficient ketosis

14/24

Hypoglycemia

3/24

Hyperketosis

3/24

High Bilirubin

1/24

Others: - no complications - pancreatitis - multi systemic organic failure - general electrolyte abnormalities - instability of solution by Mg and Ca

2/24 1/24 1/24 1/24 1/24

In summary: based on the evidence and clinical practice it is clear that during KD-PN complications

are frequently seen even if PN is only given for a few days. Most complications are transient and can

be avoided by the use of strict ICU protocols. This highlights the need for slow introduction of KD-PN

based on the international PN guidelines with tailoring of ratio, fat, protein and carbohydrate

depending on liver function and evidence of hyperketosis and/or hypoglycaemia.

Initiation during Propofol anasthesia is a semi-contra indication (related to the high lipid content) and

should be handled with caution and with strict monitoring of lipids, renal, cardiac and liver

functioning [37].

Close monitoring is of high importance (see paragraph 6.3).

39

Based on the previous information the following recommendations were formulated: RECOMMENDATIONS on complications.

6.3 Monitoring. Guidelines

-ESPGHAN/ESPEN [20]:

-Routine electrolyte, mineral (Calcium, Phosphorus and Magnesium), triglyceride and serum urea

determination help to determine nutritional deficiencies.

-Serum vitamin and trace element concentrations should be evaluated in long-term PN dependent

patients.

- Nutritional assessment must include estimates of dietary and fluid intake (oral, enteral, and

parenteral), output (urine, gastrointestinal losses), and a record of gastrointestinal symptoms

- Biochemical monitoring needs to be tailored to the underlying clinical condition and also the

duration of PN.

- To prevent general complications of PN; use ASPEN and ESPGHAN/ESPEN guidelines !

More specific:

-Adequate infection control precesses to prevent CVC – related blood stream infections:

-Hand hygiene is of the utmost importance.

-Catheter insertion with maximal sterile barriers.

-Vigorously clean hub of catheter with 70% alcohol or chloorhexidine before accessing line.

-Limit access for labs up to 1 time per day if possible.

-IV tubing changes every 24 hour for lipids and every 72 hours for PN solution unless 3 in 1 bag.

admixture change every 24 hours if this is possible within stability parameters.

-Catheter insertion and standard surveillance plan established by institution to reduce

infections.

-Prepare PN under strict aseptic handling, especially in case of tailored regimes.

-Change amino acids and glucose sets and extensions every 24-48 hours.

-Change lipids sets and extensions every 24 hours.

-Be aware of steroid, bicarbonate, diuretics and Valproate use during PN.

-Run PN (including lipids) continuously (24 hours).

-Side effects of PN during KDT that are most frequently seen are :

-elevated lipids (up to < 400 mg/dl / 10 mmol/l) ,

-insufficient ketosis (< 1.5mmol/ml)

-hypoglycaemia ( < 2.5 mmol/l / 45 mg/dl).

-to a lesser account: hyperketosis (> 6.5 mmol/l), hyperbilirubin (>40mcrmol/l),

altered liver function tests and pancreatic enzymes.

- A tailored nutritional regime must be carefully chosen and closely monitored in the

high risk group of malnourished patients.

- KD-PN initiation during Propofol anasthesia is not recommended and should be undertaken

only with caution.

40

- ASPEN [23]

- Check serum triglyceride levels with each increase of 0.5 – 1.0 g/kg per day of intravenous lipids and

weekly when the maximum dose is achieved. Check more frequently in case of critically illness or

infection

Lipid emulsions should be decreased if serum or plasma triglyceride concentration during infusion

exceeds 250 mg/dl in infants of 400 mg/dl in older children.

It is important to monitor liver function tests when lipid emulsions are given. If there is evidence of

progressive hepatic dysfunction or cholestasis a decrease in lipid supply should be considered.

Lipid supply should generally be continued at least in amounts supplying the minimal essential fatty

acids requirements which is unlikely to happen during KD PN administration.

Carnitine supplementation should be considered on an individual basis in patients receiving PN for

more than 4 weeks.

- A stepwise increase and decrease of glucose infusion rates at onset and at discontinuation of the

infusion respectively should be considered to avoid hyper- and hypoglycaemia. Glucose tolerance

should be monitored. This is also important at the time of starting cyclic PN.

- Fluid and electrolyte concentrations are usually monitored on a daily basis for the first days of

treatment, then the monitoring intervals are adapted depending on clinical status and the stability

of the patient’s condition.

- Iron is not routinely provided in PN mixtures because of the risk of iron overload. Patients receiving

long term PN (> 3 weeks) should receive iron supplements. Regular monitoring of serum ferritin is

necessary.

- Trace elements should be supplied with long-term PN (> 3 weeks) and should be periodically

monitored especially in cholestatic patients.

- Blood concentrations of Ca, Ph and Mg require periodic monitoring (no frequency mentioned).

- Fat and water soluble vitamins are necessary in PN. The guidelines give information about the

amounts of vitamins. There is no information about the frequency of monitoring.

- White paper [38]

Laboratory monitoring recommendations while on Ketogenic PN:

Laboratory assessment Frequency

Comprehensive metabolic panel, Magnesium, Phosphorus Daily until stable, then weekly

Triglycerides, amylase, lipase Daily until stable, then weekly

Serum betahydroxybutyrate Daily until stable, then weekly

Carnitine, free & total Baseline, then every 2 weeks

Zinc & Selenium Every 2 weeks (if supplementing)

Urine ketones (optional) Every day

41

Literature Reported advice for monitoring of PN during KD are summarized in table 16.

Table 16 Mentioned or reported laboratory assessment during Ketogenic PN.

Study Population Nutritional parameters and laboratory assessment


5-year-old patient with intractable diarrhea. KD-PN with MCT fat was used

Liver function test, Iron, triglycerides, cholesterol

Jung, D.E et al,

(2012)

Retrospective study [8]

10 children Age: 1.1-11.7 years, 7 boys/3 girls

Weight, intake/output Electrolyte, glucose, serum betahydroxybutyrate, BUN/Creatinine, Ca, Phosphorus, Magnesium, Triglyceride, liver function test, amylase/lipase. Remark: they checked these parameters in the morning after 8 hours with a glucose free solution and before initiating the ketogenic parenteral nutrition during 16 hours.


21 year old patient with SRSE

serum beta-hydroxybutyrate, acetoacetate



Tests before the start of the KD-PN: Serum carnitine, lactic acid, pyruvic acid, fatty acids, chemistries, lipids, electrolytes, complete blood counts, vitamin A, D, E and K levels. During TPN: electrolytes, arterial blood gases, urine ketones

Chiusolo, F. et al (2016) Single case as part of a retrospective review [11]


Glucose, ketone bodies, Cholesterol, triglycerides NEFA, uric acid, Creatinine, Albumin, ALT, AST, gGt Amylase, lipase Sodium, Potassium, Calcium, Phosphate

Farias-Moeller ,R. et

al (2017)

2 cases as part of a retrospective study [13]

2/9 children with SRE (both 5 y)

Tests before the start of the KD-PN: CBC, CMP, Mg, Phosphorus, plasma acylcarnitine profile, urine organic acids, plasma amino acids, carnitine free & total, 25-hydroxy vitamin D3, Zn and Se. During TPN: BMP, Mg, Phosphorus, UA, blood glucose, urine ketones

Dressler, A et al (2017) Retrospective study [14]

17 children Median age 1.8 years

Glucose, ketones, lipids pattern, blood count, liver function on daily basis, after 1 month and every 3 months during KD treatment

42

Expert opinion

The survey on 24 international expert teams from 8 countries report laboratory parameters during

KD PN of ketones, glucose, lipid profiles, bloodgas, electrolytes, liver panel, renal panel, amylase,

direct Billi, carnitine, total protein, albumin, Mg, P, Ca, Cu, Hb, (Se, Zn, vit.D). There is a wide range in

the frequency of required laboratory parameters between the several expert teams.

In summary: little data has been published in this area. Therefore this chapter cannot provide fully

evidence based recommendations but will try to provide a reasonable framework for the therapists

who prescribe PN during KDT.


If the patient starts the KDT as PN at the ICU, the initiation is proceeded by baseline checks:

NOTE: remember to spare an extra blood sample!

Table 17A. Recommendations on baseline checks for new start KDT as PN

- Anthropomethrics (weight, height, head circumference <1 year)

- Dietary intake and output.

- Complete blood count with platelets.

- Electrolytes to include serum bicarbonate, total protein, Calcium, Zinc, Selenium,

Magnesium, Phosphate.

- Trace elements; zinc, selenium, copper, CRP.

- Serum liver and kidney tests (including albumin, AST, ALT, blood urea, nitrogen, creatinin.

- Fasting lipid profile.

- Serum acylcarnitine profile.

- Urine analysis.

- Urine calcium and creatinine.

- Antiepileptic drug levels (if applicable).

- Check if all contra indicated metabolic disorders are excluded.

During initiation:

- Glucose daily/ every other day.

- Betahydroxybutyrate (BHB) daily /every other day.

43

If the patient is already on the KDT and commences PN, the following checks are needed at initation

and during PN. NOTE: remember to spare an extra blood sample!

Table 17B. Recommendations on monitoring during Ketogenic PN

Item <1 year age unstable

<1 year age stable

> 1 year age unstable

> 1 year age stable

Weight daily weekly 2 x week weekly

Height weekly monthly 1 x 2 weeks 1 x 3 months

Head circumference 1x 2 weeks monthly - -

Intake / output daily daily daily daily

Seizures daily daily daily daily

Blood

Blood gas and osmolality daily 2-3x week daily 2x week

Na, K, Cl daily 2-3x week daily 2x week

Ca, Mg, Ph daily 2-3x week daily 2x week

Copper monthly monthly monthly monthly

Complete blood count unknown weekly unknown weekly

Albumine daily 2 x week daily weekly

Glucose¹ 1 x 4 hours 2-4 x day 1 x 4-6 hours 1-3 x day

Billirubin total/direct daily 2 x week daily weekly

ASAT, ALAT, ALP 2 x week 2 x week weekly weekly

Amylase/lipase unknown weekly unknown weekly

Urea daily daily daily 2 x week

Creatinine daily daily daily 2 x week

Triglycerides² daily weekly daily weekly

Beta-hydroxybutyrateᶟ daily daily daily daily

Carnitine free / total unknown 1x 6 months unknown 1x 6 months

Lipid profile daily when lipids off for 4 hours.

monthly unknown monthly

Hb weekly weekly weekly weekly

Serum ferritin monthly monthly unknown monthly

Vit. A, D 25-OH monthly monthly monthly monthly

Vit. B1, B12 1 x month monthly monthly monthly

Folic acid, Zn, Al 1 x 6-12 months 1 x 6-12 months 1 x 6-12 months 1 x 6-12 months

Cu, Cr, Mn at indication at indication at indication at indication

Se monthly 1 x 6 months unknown 1 x 6 months

Urine

Na weekly monthly monthly monthly

K weekly monthly monthly monthly

Calcium/creatinine ratio weekly monthly weekly monthly

Urine ketones 4

(at indication)

every day 2 x day Every day 2 x day

Osmolarity weekly monthly monthly monthly

Explanation: ¹: Glucose levels of 2-2.5 mmol/l (approximately 40-45mg/dl) should be treated immediately with 2-4 gram of

carbohydrates (20-40 ml glucose 10%). Blood glucose should be re-checked 15-20 minutes after treatment and if not

improved a futher dose is given until the glucose level is above 3 mmol/l (approximately 55 mg/dl).[51]

²: The upper limit for triglycerides is 10 mmol/l (approximately 387 mg/dl). At a level of 5 mmol/l (approximately 200

mg/dl) start carnitine 50 mg/kg with a maximum of 1 gram/day [52].

44

ᶟ: The goal is within the range of 2-5 mmol/l beta-hydroxybutyrate (approximately 20-52 mg/dl) 4 : Ideal range is 8-16mmol/l or 3-4+ : the exact level depends on type of urine dipstick.

45

Chapter 7 Evaluation of Risk-Benefit of Ketogenic Parenteral

Nutrition.

By Dr Stéphane Auvin and Dr Helen Cross

The evaluation of KD-PN is based on an assessment of the efficacy, the ketosis, the side effects and

the medical reason for its application. Therefore, the evaluation of the effects of the KD-PN will be

different according to the indication. When parenteral adminsitration is utilised due to enteral KDT

provision not being possible, evaluation will be based on the maintenance of the seizure control

provided by the initial enteral administration of the KD. The seizure frequency based on a diary of the

various seizure types, as well as the EEG recording in some epilepsy syndromes, will be the main

criteria for the evaluation of KD-PN. Similar criteria would be helpful to evaluate the effect of a KD-

PN initiation for any epilepsy syndrome. Careful evaluation of the medical situation (i.e underlying

disease, laboratory checks) is essential to evaluate that PN use is safe and to determine if the enteral

KDT may be reintroduced.

When the KD-PN is used for a refractory status epilepticus including FIRES, other criteria will be used

such as reduction of continuous EEG discharges on EEG monitoring, cessation of seizures, ability to

stop an anesthesic agent used for a refractory SE without SE recurrence or prolonged seizure

recurrence. When an anesthesic agent is used to treat a refractory SE, the use of continuous EEG

recording is required. Criteria to evaluate the efficacy should be both electroencephalographic and

clinical.

As mentioned above, the measurement of ketosis by BHB butyrate levels is helpful to evaluate if the

patient has made the metabolic shift to utilizing fat over carbohydrates. It could be helpful to

evaluate the maintenance of ketosis after the switch from an enteral to parenteral administration or

the appearance of ketosis after initiation of a KD-PN. There are conflicting results in the literature

about the direct correlation of the ketosis and the anti-seizure efficacy. The main goal of KD-PN is not

ketosis but seizure control; if ketones are low but the patient is doing very well (i.e. status is stopped)

no futher action is required. Therefore, this should be kept in mind in the initiation and the

management of parenteral ketogenic therapy.

As mentioned above, there are frequent side effects during the use of parenteral KD requiring the

monitoring of electrolytes, blood lipid and liver enzymes.

46

Chapter 8 Weaning from parenteral to enteral Ketogenic Diet.

By Elles vd Louw and Dorine van den Hurk.

8.1 General.

Based on the high risk profile, limitation of the PN period is of high importance: when the underlying

reason for NPO is solved, the enteral route should be used immediately. Detailed information on how

the patient may be weaned from PN is limited.

8.2 Weaning.

Guidelines

- ESPGHAN/ESPEN guidelines [20]:

-Feed should be given at normal concentrations and not diluted. -When increasing enteral feed, only one change at a time may be made, to assess tolerance. -In severe intestinal failure, feed volumes may be increased slowly, according to digestive tolerance. -Enteral feeding may be introduced as a liquid feed infused continuously by tube over 4e24 h periods, using a volumetric pump. - ASPEN [23] guidelines contain no information on weaning.

- White paper[38]: use of trophic feeds to maintain gut integrity by supplementation of MCT oil

as bolus or 2.5-5ml/4 hours en stepwise increasing based on tolerance and ketone levels. There

is no information on transition of IV towards enteral KD.

Literature

There is little information on transition from PN to enteral KD. Some studies [6, 10, 13] only mention

the enteral KD is stepwise introduced but no detailed information is given.

Information on weaning is summarized in table 18A and 18B.

Table 18A. Switch from parenteral to enteral KD.

Study Way of tapering Notes

Jung, D. et al 2012 [8]

Slowly increase of enteral feeds

No information on how this is done

Strzelczyk, A. et al 2013 [9]

Gradual introduction of Ketocal 4:1 LQ , 5 x 237 ml/day

No information on how this is done

Appavu, B. et al 2016 [12]

Start 50% of RDA of KD formula for 20 hours/day. Increased 10% each day anasthesia is tapered

- Chiusolo F et al 2016 [11] shows detailed information how they build up enteral KD after three days

KD IV shown in table 18B.

47

Table 18B.Step by step plan switch parenteral to enteral KD Chiusolo et al.

Day 4 Day 5 Day 6 Day 7

EN IV EN IV EN IV EN IV

Protein (g/kg)

0.49 0.3 0.55 0.50 0.84 0.40 1 0.25

Lipids (g/kg)

2 1.85 3 1.85 4 1.50 5 0.93

Carbs (g/kg)

0.13 - 0.13 0.17 - 0.20 -

Ratio

3.0:1 3.7:1 4.0:1 3.7:1 4.0:1 3.7:1 4.0:1 3.7:1

Ketones (mmol/l)

3.2 4.3 3.2 4.9

Expert opinion

There is no detailed information from the international survey: weaning is done on individual basis

and most centers use trophic feeds as KD formula, only 33% use MCT oil.

In summary: the way PN may be weaned has to be individually designed and based on the medical

situation and nutritional status of the patient.

In general, the duration of the PN will determine the volume of enteral feeding that will be used for

the steps and the duration of the total weaning process.

48


RECOMMENDATIONS for Ketogenic PN weaning.

- Start trophic feeds as soon as possible and appropriate.

suggestions for application are:

- maximum of 5% of calculated enteral KD formula or 20ml/kg/day continously (this is dependent

on age and fluid requirement, and calorie requirement).

- dependant on ketogenic regimen, GI tolerance, and local decision 2.5-5ml/4 hours MCT oil may

be given as a bolus and increase this amount based on tolerance and ketone levels .

- In case of no/minor malabsorption and/or short term full KD-PN (few days- 2 weeks):

step 1: start with 25-33% of enteral KD formula, decrease KD-PN.

step 2: increase enteral KD formula to 50-66%, decrease KD-PN.

step 3: increase enteral KD formula to 66%-75%, decrease KD-PN.

step 4: at 75% enteral, KD-PN can be stopped.

Make 1 step every 1-2 days based on tolerance and ketone levels.

- In case of mild/severe malabsorption and/or long term full PN (> 2 weeks):

step 1: start with 10-20% of enteral KD formula, decrease KD-PN.

step 2 and on: increase enteral KD formula with 10-20% each step and decrease KD-PN based on

tolerance.

Final step: at 75% of enteral, KD-PN can be stopped.

Make 1 step every 3-4 days based on tolerance and ketone levels.

OR

- Start with 5-10ml of enteral formula and decrease KD-PN volume.

At 75% of enteral formula the KD-PN may be stopped.

Advice: add (extra) MCT emulsion up to 10 en% to the enteral formula to boost ketosis if required.

49

Chapter 9. Conclusions.

By Dr. Stéphane Auvin and Dr. Helen Cross.

This work is of a particular interest because of the absence of guidelines for the use KD-PN until now.

Based on the available guidelines for PN, the available publications on KD-PN, an international survey

and a consensus approach, we are now able to propose a document that would support the use of

KD-PN when required.

However, it would be important to move to the next steps by providing new data on KD-PN

application. Obviously, prospective and controlled studies are required to prove efficacy and safety

of KD-PN application based on these guidelines. One of the first steps could be to consider an

international registry collecting the cases of patients treated by KD-PN. In addition, most studies

include only patients on KD-PN for several days; long-term data are lacking. More data would be

helpful to update these recommendations in the near future.

KD-PN calculation, initiation, monitoring and weaning is shown in a flow chart (see Appendix I)

50

Funding and Disclosures. The project group was supported financially by Nutricia (travel and hotel costs only) to attend the meeting at the

DMIMD 2017 in London.

All authors have seen and approved the final manuscript.

All authors declare recieving no financial support.

51

Appendix I Flow chart of consensus ketogenic parenteral nutrition application Aim : Ketogenic Parenteral composition with the highest diet ratio possible with the lowest complications and maximum effect on seizure reduction.

Step I: Preparation Page Step II: Design Page Step III: Initiation Page Step IV: Monitoring Page

Collect data of: Medical history and background

Diagnosis. Indication for KD therapy:

-allready on KD: level of seizure reduction -newly start KD: current level of seizures, contra- indication.

Enteral route prohibited for > 48 hours.

Anthropometrics. Acute medical situation. Nutrition history/allergies.

Cave: - Laboratory checks for contra indications - Malnutrition - Concomitant medication (IV). - Carbohydrate content of medication (IV) -Current enteral intake, output and route.

14-15

Use international guidelines! --> Individualize for Ketogenic therapy Determine: 1. Fluid volume available for TPN cave: fluid for medicaton ,fluid restriction, lab checks. 2. Caloric goal cave: BMR, risk for hyper alimentation 3. Carbohydrate goal cave: dextro/glucose use, glycerol content 4. Protein goal cave: malnutrition, acute illness, ideal weight 5. Lipids/ Diet ratio goal cave: aim for the highest possible, include glycerol 6. Additives cave: individualize for RDA/age/weight 7. Ketones cave: level of ketosis needed for seizure reduction.

17-18 18-21 21-24 24-26 26-28 29-31 42-43

KD-PN prescription: 1. Write individualized step by step plan for initiation. 2. Follow hospital and pharmacy protocols and procedures exept for carbo hydrates and lipids. 3. Start trophic feeds when whenever possible.

31-34 6 48

Use international guidelines! Screening for side effects: 1. Insufficient ketosis. 2. Hyperketosis. 3. Hypoglycemia. 4. Hyperlipids. 5. Minerals at risk. (Ca, Mg, Ph) 6. Liver panel. Cave: -CVC infections -anthropometrics -seizure reduction -medical situation

34-44

Step V: Weaning

Restart enteral feeding as soon as possible: individualize a step by step plan based duration PN, tolerance and level of ketosis. (page 48)

52

Appendix II: Calculated case reports.

1. Ketogenic TPN Case Report by Jessica Harvey, RD, Cincinnati Children's Hospital, Cincinnati, USA.

Patient: Age: 5 years old Sex: Male

Medical History and Background:

Patient with a history of intractable epilepsy with multiple seizure types (generalized tonic clonic,

complex partial, atonic, myoclonic jerks), s/p PEG tube placement and on the ketogenic diet.

Returned to the emergency department post PEG placement with 2 day history of G tube drainage

progressively worsening that turned foul smelling and presumably feculent. Small segment of

catheter between the external stopper and internal PEG tube bumper may indicate PEG tube

traversing a bowel loop. Pt was taken to the operation room for diagnostic laparoscopy. Procedural

findings of G tube entering side wall of colon and posterior wall of stomach.

Patient was admitted for post-operative management, bowel rest (requiring NPO), and to start

ketogenic PN via a peripheral line for at least 7 days.

Objective:

To calculate a ketogenic PN formulation to the highest ratio possible within established guidelines.

Anthropometrics:

Weight: 20 kg (z-score: 0.62)

Height: 112.5 cm (z-score: 0.78)

BMI: 15.8 kg/m2 (z-score: 0.31)

Ideal body weight: 20 kg

Current enteral medications:

Onfi, ® Klonopin®, ½ packet Cytra K crystals BID®, 250 mg carnitine 2x/daily, Multivitamin,

Depakote®

Current enteral ketogenic diet prescription:

920 ml KetoVie vanilla®

730 ml water

4:1 ratio

Provides: 1300 calories, 31 g protein, <1 g/CHO

Run at 75 ml/hr x 22 hours via G-tube

To calculate ketogenic PN:

Step 1 Determine fluid needs

Patient does not have any other drips.

Maintenance fluid needs based on Holliday-Segar equation = 1500 mL/day

Step 2 Determine calorie goals

Ideally patient would get at least 75% of enteral calorie goals which would be about 975 calories/day.

53

However, this may not be feasible to get highest ratio possible.

Step 3 Determine protein goals

This patient just had surgery so plan to start at 1 g/kg. If you would like to get ratio higher, may

decrease protein down to 0.8 g/kg 1 g/kg = 20 g = 80 calories.

Step 4 Determine lipid goals

Would like for goal to be 4 g/kg/day which is 400 mL, 80 g lipid, and 800 calories.

Determine grams of glycerol from lipids (2.25% glycerol in 20% Intralipid) = 9 g CHO (180 calories) .

Calculate lipid infusion rate: 0.16 g/kg/hr, with a goal of <0.17 g/kg/hour.

Consider starting day 1 with half goal lipids and increase to goal on day 2.

Alternatively, start at 1 g/kg lipids and advance by 1 g/kg daily until goal is reached.

Institution policies may vary.

Step 5 Determine final ratio

80 g of fat : 9 g from glycerol + 20 g protein = 2.75:1 ratio.

Step 6 Determine final calorie intake from PN

800 calories from lipids + 80 calories from protein + 0 calories from dextrose .

= 880 calories/day which is about 68% total enteral calories .

Step 7 Additives

Multivitamin .

Carnitine 500 mg .

Consider acetate, if Bicarbonate level drops .

Step 8 Lab monitoring

Sodium, Potassium, Cloride, Calcium, Magnesium, Phosphorus, CO2, Albumin .

daily until electrolytes stable and then two times weekly.

Blood glucose every 6-8 hours.

Urine ketones 2x/daily.

Initially and then weekly Triglycerides (Goal of < 1000 mg/dL ).

CBC w/diff .

Amylase and lipase weekly.

Beta-hydroxybutyrate daily.

Once (if not drawn in the past 6 months):

Carnitine (free/total), Selenium , Zinc ,Copper,Vitamin D25OH.

Step 9 Transition back to enteral feeds as able

Suggested transition:

Start with 10-20% of enteral KD formula, decrease PN 1:1

Increase enteral KD formula with 10-20% each step and decrease TPN based on tolerance.

Once at 75% enteral feeds, PN can be discontinued.

54

2. Ketogenic TPN Case Study:by Vanessa Aldaz MPH RD CDE, Rady Children's Hospital, San Diego,

USA.

Base solution

Other items

Volume (ml)

Kcal Fat (gram,Kcal)

Protein (gram,kcal)

Carbs (gram,kcal)

Diet ratio

20%

Intralipid®

4.0 g/kg 400 mL 800 kcal 80 g (800 kcal)

- 9 g (30.6kcal)

Travesol

10%®

1.0 g/kg 200 mL 80 kcal - 20 g (80 kcal)

-

Dextrose 70%

0% - - - - -

Total 880 kcal 80 g 20 g 9 g 2.75:1

Enteral nutrition

- - - - - -

55

Patient: Age: 4 y old Sex: Male.

Medical History and Background: Trisomy 21, g-tube dependent, on Ketogenic diet treatment, hx of

Hirschsprung’s disease s/p pull through, intractable epilepsy with infantile spasms, and h/o bilateral

grade 2-3 VUR s/p deflux 2014 with residual renal scarring who is presenting with three days of non-

bloody diarrhea, non-bloody vomiting (described as looking green), intolerance of feeds, and

decreased Urine output.

Patient admitted for bowel rest (NPO), and rule out Possible C-diff or Norovirus.

Anthropometrics:

Weight: 15.1 kg (33 lb 4.6 oz). 54 %ile (Z= 0.10) based on Down Syndrome (2-20 Years) weight-for-

age data.

Height or Length: (!) 87 cm (2' 10.25"). 5 %ile (Z= -1.67) based on Down Syndrome (2-20 Years)

stature-for-age data .

Body mass index: 19.95 kg/m². >99 %ile (Z= 2.74) based on CDC 2-20 Years BMI-for-age data .

Current Medications (enteral): 800 international units vitamin D3, Prevacid®- 330 mg, Carnitor®

twice daily, Omeprazole®, 500 mg Calcium- 3 times daily.

Home Ketogenic Diet supplements:

Nano VM® 1- 3yrs (Solace Nutrition) =1 scoop per day.

Bicitra®= 25 ml 4 times per day.

Vitamin D3-2 drops of 400 IU

Carnitor®-3 ml 2 times per day.

Allergies: note for pharmacist : carbohydrate, dextrose and glucose for purposes of ketogenic diet.

Current Enteral KD Prescription Diet:

Ketogenic diet type: classic at 3.16:1 ratio, g-tube,feeds

Feeds via g-tube boluses:

170 ml formula + 20 ml water per feed 4 times per day. Flushes 60 ml water.

Noc: 500 ml formula at a rate of 60 ml/hr, flushes after feed with 60 ml

Ketogenic Diet recipe RX: Ketocal 4:1 LQ

Recipe = Ketogenic diet: 3.16:1

6 g Sol-Carb® powder.

570 ml KetoCal® 4:1 LQ-vanilla/unflavored.

600-610 ml water.

Total volume= 1180 ml (39.33 oz).

Mix water into KetoCal Liquid, ® stir or shake well.

Total formula volume=1180 ml at 22.2 cal/oz.

Recipe provides = 867 kcal/day at a 3.16:1 ratio (meets 100% nutritional needs).

Protein= 17.61g (1.31g pro/kg/day).

Fat= 84.4g.

56

CHO=9.13g.

Estimated Nutrition Requirements:

Calories: 55-75 kcals/kg/day due to nutrition status and condition.

Protein: 1.09 g/kg/day.

Fluid: 1255ml/day (Holliday-Segar method).

Diet Order: NPO X 5 days for bowel rest

Problem identified and Need for starting KD PN: unable to tolerate g-tube feeds at this time,

(currently running at 10 ml/hr X 24 hrs at ½ strength) attempted water and dilute Pedialyte.

Attempted ¼ strength formula but minimally tolerated. Unable to tolerate increase in

concentration and rate. PICC line placed.

After attempting both ¼ and ½ strength continuous feeds for 3 days, pt was unable to fully tolerate

and receive adequate nutrition therefore decision to start KD-PN was made. Patient continued with

emesis and diarrhea.

½ strength formula running at 10 ml/hr x 24 hrs received only 86 calories per day (0.9% total calorie

goal).

Patient is not meeting nutritional needs and at risk for malnutrition.

Nutrition Intervention

To Calculate KD-PN:

List any precautions pertinent to ketogenic diet:

No carbohydrates or dextrose. Only normal saline and electrolytes in IVF.

Please check with neurology (keto team) before prescribing any carbohydrate containing medications

as this may alter ketosis.

Continue NPO for bowel rest.

Suggest the following recommendations for KD-PN:

Step 1: Determine fluid needs

15.1 kg ( 50 ml X 5.1 kg + 1000ml)=1255ml

Use Holliday-Segar daily fluid requirements to set fluid goals.

Fluid: 1255 ml/day (Holiday-Segar method): 52 ml x 24 hrs =1248 ml/day maintenance or per

nephrology.

Step 2: Determine calorie goals

Ideally patient should get at least 75% of enteral calorie goals which would be about

650 calories/day in this case. However, this may not be feasible to get highest ratio possible.

Try to reach at least 50% of calories, if possible.

-Day 1:

No dextrose. 0%, will only be calculating final calories from protein and lipids.

Step 3: Determine Protein goals

- Day 1: 10% amino acids= 1 g/kg/day= 15g amino acids=60 kcals.

- Day 2: avanced to goal and increase protein: to 1.5g/kg/day=22.5g amino acids= 90 kcals

57

Step 4: Determine Lipid goals

20% lipid emulsion= use SMOF lipid ®only for ketogenic diet patient.

Start with 1.5 g/kg SMOF lipid®= 22.5 g lipid=225 kcals from lipid.

-Day 2: advanced to goal by increasing lipids: Increased to 3 g/kg/d 20% SMOF lipid® emulsion

= 45 g lipid x 10 kcal/g=450cal.

Goal= 225 ml lipid to run over 20 hours.

Step 5: Calculate Final Ratio

Ratio calculating glycerin= 2.5% glycerol in SMOF lipid®, contains 5.62 g carb; so, 45g fat:5.62g from

Glycerol carbohydrate (C) + 22.5g protein (P)=45g Fat/28.12g C+P= Final ( calculated with glycerol

carbohydrate from lipids) ratio= 1.6:1

Step 6: Final calorie intake from PN

Goal PN provides= 2:1 Keto ratio, 540 calories (62.2% of goal calories), 1.5g protein/kg

Dextrose 0%, provides no calories.

-Day 1: provides 285 kcals (225 lipid +60 protein), (33% goal calories).

-Day 2: provides 540 kcals (450 lipid + 90 protein), (62% goal calories).

Step 7: Additives

Standard pediatric MVI and trace minerals for age.

Carnitine 20 mg/kg/day.

Step 8: Lab Monitoring

Patient to maintain ketosis:

Urine ketones in AM and PM or Q VOID. Goal urine ketones: moderate to large (80).

Check B-OHB daily. Goal serum Beta-hydroxybutyrate= 4-6mmol/L.

Check daily complete metabolic panel.

TPN labs (lipids (TG), Calcium, Magnesium, Phos, LFT's).

Maintain Blood glucose (BG)-non-fasting: 50-85mg/dL.

Urine ketones: 60-160 (moderate to large).

Blood ketones (Beta-hydroxybutyrate):4-6 mmol/L (acceptable ranges 3-7mmol/L).

Urine specific gravity (USG):1.010-1.020.

Urine pH: 6-8.

CO2 >20 mmol/L.

Establish inpatient hypoglycemia guidelines for ketogenic diet patients.

Maintain Blood glucose (BG)-non-fasting: 50-85mg/dL.

Ensure TG checked when lipid off x 4 hours.

Goal is to maintain ketosis.

Step 9: Transitioning back to full Enteral feeds (GTube), weaning off KD.

Resume G-tube feeds as medically able:

Re-introduced feeds slowly ( trophic feeds ) ¼ strength keto formula at 5 ml hr x 24 hours and

advanced to ½ strength when goal rate was reached at 49 ml/hour.

Continued advancing as tolerated to ¾ strength and then to FS.

Progress to home G-tube feeds as tolerated:

Daytime feeds: 170 mL formula + 20 mL water per feed 4 times per day.

Enteral feeds: 500 mL formula at a rate of 60 mL/hour.

Flush with 60 mL water after each feed.

58

Step 10: Calculate any other calories (enteral feeds as applicable)

-Day 14: PN at 37 ml/hr + GT trophic feeds

Volume-52ml/hr=1248 ml (85.5ml/kg/d)

Amino acids= 1.5g protein/kg/day= 22.5g protein/day

Lipid at 43 g per day at 10.8ml/hr over 20 hrs. = 3 g lipid/kg/day

Provides= 90 cal + 430 cal from fat=520 kcals (80% of goals)

37 ml/day = 64 + 430=494 kcals

Calories from GT= 15ml/hour at 1/2 strength=360 ml= 0.37 kcal/ml X 24 ml= providing 133 kcals.

Nutritional Intake of 24 hours.

494 PN + 133 GT=627 kcals (73% goal kcals of 867 kcals).

Further evaluation/Discussion:

Patient tested positive for Norovirus. Patient continued on KD- PN for 14 days. At day 8 Trophic feeds

restarted at 5ml/hr with ¼ strength concentration and increased as tolerated to ½ strength, however

continued with some diarrhea. Pectin (Certo Liquid®) was added to formula at 2% total volume for a

few days. Home diet and trophic feeds were advanced slowly to FS formula at 49 ml/hr with 2%

Pectin (Certo Liquid®) and IGG IV injections given for Norovirus. Stool output decreased and PN was

slowly weaned off asGT trophic feed volume was increased slowly to goal. Patient was advanced to

home regimen , pectin was removed from the formula and continued at continuous rate at full

strength before consolidating to home bolus schedule.

The addition of pectin, although containing citric acid which is metabolized as a carbohydrate did not

seem to affect ketosis levels ( BHB > 3mmol/L) at that time of administration most likely due to his

hypocaloric status while tapering off TPN and onto EN. Addition of Pectin is not standard of practice

in ketogenic patients but in this case it did demonstrate helpful in alleviating diarrhea/stool output

and to have no ill effects to ketone levels or seizure control, perhaps due to limited calorie intake

during the time of transition to home diet goals.

Base solution

Ordered items

Volume (ml)

Kcal Fat (gram,Kcal)

Protein (gram,kcal)

Carbs (gram,kcal)

Diet ratio

Normal saline

0% dextrose

n/a n/a n/a n/a n/a 0

10% travasol

1.5g/kg 22.5 g 90 kcal

0 22.5g (90 kcal)

0

20% IL SMOF

3.0 g/kg 225 ml 450 kcal

45g (450 kcal)

0 5.62g (22.5 kcal)

1.6:1 (with glycerol)

Total 540 kcal

45 g 22.5g 5.62g 2.0:1 (without glycerol)

3. Ketogenic TPN case calculation by Eimear Forbes, RD, Temple Street Hospital, Dublin, Ireland.

Sample Medical History and Background:

59

Patient 7yr old boy to PICU in status epilepticus. Unknown cause ? FIRES . For Patient Specific PN

due to ileus. Neurology and PICU Team wish to start ketogenic diet. Patient intuBated and ventilated

Objective:

To calculate ketogenic PN formulation within established guidelines to achieve ketosis for new

critically unwell patient starting on ketogenic diet. On 80% Fluid requirements total.

Anthropometrics:

Weight: 27 kg (50-75TH C).

To calculate ketogenic PN:

Step 1 Determine fluid needs and availability

80% fluid maintenance based on Holliday Segar Equation = 1640mls x 80% = 1312ml.

However need to calculate fluid available when medications and infusions taken into account

Total medication and infusions volume = 300ml.

Therefore 1012mls available for IV fluids and Patient Specific PN when available.


As patient is intubated and ventilated, will aim for BMR initially.

BMR: 1117kcal (41.4kcal/kg).


Aim to provide minimum 1.0g/kg but ideally 1.5g/kg depending ketosis and ketogenic ratio.

Step 4: Determine desired ketogenic ratio and macronutrient prescription

(Based on 1g SMOF Lipid® 20% = 10kcal, 1g Prot / Amino Acid= 4kcal and 1g CHO 4kcal. Source of

carbohydrate and protein may differ between different compounding units, which may alter the

calorie composition. )

Fat (/kg) Protein (/kg) CHO (/kg) KD Ratio Kcal / kg

1.0 1.0 4.0 0.2:1 30

1.5 1.0 4.0 0.3:1 35

2.0 1.0 4.0 0.5:1 40

3.0 1.0 4.0 0.6:1 50

4.0 1.0 4.0 0.8:1 60

1.0 1.0 3.0 0.25:1 26

1.5 1.0 3.0 0.37:1 31

2.0 1.0 3.0 0.5:1 36

3.0 1.0 3.0 0.75:1 46

4.0 1.0 3.0 1.0:1 56

1.0 1.0 2.0 0.33:1 22

1.5 1.0 2.0 0.5:1 27 A

2.0 1.0 2.0 0.66:1 32

3.0 1.0 2.0 1.0:1 42 B

4.0 1.0 2.0 1.33:1 52

1.0 1.0 1.0 0.5:1 18

1.5 1.0 1.0 0.75:1 23

2.0 1.0 1.0 1.0:1 28

3.0 1.0 1.0 1.5:1 38 C

4.0 1.0 1.0 2.0:1 48 D

60

1.0 1.0 0.5 0.66:1 16

1.5 1.0 0.5 1.0:1 21

2.0 1.0 0.5 1.33:1 26

3.0 1.0 0.5 2.0:1 36

4.0 1.0 0.5 2.66:1 46 E

Use the above table to help determine macronutrient order for PN based on nutritional needs.

Suggest starting at B, then daily proceed to C and then D and e. However if concern re biochemical

markers (eg triglycerides, Blood glucose levels) initially may wish to start with A before progressing

daily to B, C, D, E.

May not be possible to progress on ratios depending on biochemical markers (eg triglycerides, Blood

glucose levels).

If additional calories required may need to lower ratio.

The ml/kg required to provide the macronutrient will depend on the PN solution constituents

including the macronutrients and micronutrients and electrolytes. In some situations it may not be

possible to provide all the desired macronutrients if patient is fluid restricted.

The above is only a suggested guide and will be dependent on patients clinical condition, ketosis and

blood glucose levels, fluid availability as well as biochemical markers.

The above calculation is based on SMOF Lipid®; glycerol content not calculated.

Step 5 Additives Electrolytes : Sodium, Potassium, Calcium, Phosphate and Magnesium

Vitamins and Minerals: Peditrace ® - 15mls total; Vitlipid N Infant ® - 10mls total; Solvito N ® - 10ml

total.


Full pre Ketogenic biochemistry screen including vitamin and mineral profile.

Full U&E, Bone Profile, Liver Function tests including Triglyceride, Blood Gas daily until stable

Blood Ketones and Bloods Sugar Levels – 6hourly.

Additional testing: Amylase (if high triglycerides), Carnitine, Triglycerides and lipaemic index markers

are important and often in Ketogenic Patient Specific PN triglycerides levels will increase and

lipaemic index markers will be affected, therefore this may require a lowering of fat and increase of

protein and carbohydrate and hence a reduction in ketogenic ratio and ketogenic diet when patient

is on Ketogenic Patient Specific PN.

This must be monitored closely and discussed with PICU and Neurology team regarding management

of same and overall condition.

Step 7 Transition from Ketogenic PN and Ketogenic enteral feeds

Suggested transition:

Calculate ideal and devise enteral feed recipe, volume (based on fluid permitted), ratio (based on

current ketosis and tolerance of diet), macronutrients required. In this case likely that higher

ketogenic ratio will need to be provided by feed than PN to achieve ketosis (eg 3:1 ratio).

When patient tolerating 5-10% of feed, begin to decrease PN volumes accordingly calculating overall

ratio at each step of ketogenic wean. As PN wean, ketogenic ratio will increase.

4. Case calculation by Baheerathi van de Bor & Venetia Simchowitz , Great Ormondstreet Hospital,

London , UK.

61

Patient , Age: 9 years Gender: Male

Medical history and background:

Patient admitted to pediatric intensive care (PICU) with FIRES. Patient is mechanically ventilated

requiring intensive care support. All medical therapies trialled including the ketogenic diet via

nasogastric tube, which was terminated secondary to patient not tolerating feeds and high aspirates

that were coffee-ground stained. Patient planned to start ketogenic TPN.

Plan

Calculate a ketogenic PN formulation to the highest possible ratio of 3:1 within the restrictions of a

stable PN regimen.

Anthropometric

Weight 35kg.

Requirements

BMR 1299 calories (kcal)

Protein 1.2-2.4g/kg (42 – 84g/day) (ESPGHAN guideline).

Minimal protein requirements 0.92g/kg (31.5g/day).

Enteral ketogenic diet prescription

3:1 Ratio

1299kcal.

31.5g protein.

126g fat.

10.5g carbohydrates.

Original Feed Recipe

191g of 3:1 KetoCal® powder.

Add water to total volume of 1100ml.

To give 1050ml which will provide 1274kcal, 28g protein with plan to optimise feeds as patient

tolerates feeds.

To calculate ketogenic TPN:

Step 1 Determine fluid requirements

Maintenance fluid needs based on Holliday-Segar equation = 1800ml per day.

However to check fluid allowance with PICU team, 1000mls available for PN.


BMR as described above.


ESPGHAN guidelines for age suggest 1.2-2.4g/kg/day however minimal safe protein requirement

calculations was used to achieve 3:1 ketogenic ratio.

Step 4 Determine lipid goals

62

Aim for 3.23g/kg/day in 565ml, 113g lipid, and 1130 kcal.

Determine grams of glycerol from lipids (5% glycerol solution in 20% SMOF lipid® ): 10.5g CHO

(42 kcal).

Calculate lipid infusion rate.

Consider starting at 1g/kg/day and increase by 1/g/kg/day as tolerated (check biochemistry).

Start at 1:1 ratio.

Determine final ratio

113g fat: 26g glycerol: 31.5g protein: 10.5g carbohydrate (3:1 ratio).

Determine final calorie intake from PN

1130 calories lipids (including those from glycerol = 104 kcal): 126 kcal protein: 42 kcal glucose (1298

kcal) .

Base

solution

Other items Volume

(ml)

Kcal Fat

(gram,Kcal)

Protein

(gram,kcal)

Carbs

(gram,kcal)

Diet

ratio

20% SMOF

lipid®

Glucose 70%

Vamin 18 EF

WFI

Additives

Additives

(Vitamins,

Trace -

elements

Electrolytes)

425

98

292

120

65

1296 89.6

(896)

31.5

(126)

68.5

(274)

1:1

20% SMOF

lipid®

Glucose 70%

Vamin 18 EF

WFI

Additives

520

39

292

84

65

1296 106

(1060)

31.5

(126)

27.5

(110)

2:1

20% SMOF

lipid®

Glucose 70%

Aminoven 25

WFI

Additives

560

15

204

156

65

1298 113

(1130)

31.5

(126)

10.5

( 42)

3:1

Step 7 Additives

Multivitamin.

Consider adding acetate to the PN, if metabolically acidotic to reduce chloride intake.


Sodium, Potassium, Chloride, Calcium, Magnesium, Phosphorus, CO2, Albumin daily until electrolytes

stabilise and then two times weekly.

Blood glucose every 2-4 hourly when unwell and treat levels < 3.0mmol/l.

Blood Betahydroxybutyrate twice daily.

Triglycerides daily with each increase of lipids and then weekly once established on goal rate

63

(aiming for <4.0mmol).

Amylase and lipase weekly.

Monthly (trace elements and fat soluble vitamins with iron)

Selenium, Zinc, Copper, Vitamin D25OH, Vit A/E

Step 9 Transition back to enteral feeds as able

Usually started at 5-10 ml/hr x 24 hours and gradually built up to goal rate (titrate with PN

accordingly).

Suggested transition

Start trophic feeds at 5ml/hr x 24 hours.

Increase every 4-6 hourly by 5-10ml as tolerated.

Titrate with PN 1:1 and discontinue PN once goal enteral rate achieved.

Appendix III. Outcome of international survey results.

64

Responding centers N= 24

Countries N= 9

Canada, Denmark, England, France, Germany, Ireland, the Netherlands, Sweden,USA .

On average, how many patients do you start on ketogenic PN per year?

N= 24 n

0-3 ketogenic TPN per year 17 71%

4-10 ketogenic TPN per year 7 29%

For what reason (s) do you start ketogenic PN? Check all that apply.

N=24 n

Bowel Rest 13

Refractory Status Epilepticus 13

Intercurrent illness (with GI issues > 3 days) 10

Surgery (ie: post op ileus) 15

Additional reasons other than those above 3

In what time frame do you consider starting ketogenic PN?

N = 24 n

If needing to be NPO for 24 hours

1 4%

If needing to be NPO for 48 hours

6 25%

If needing to be NPO for >72 hours

11 46%

Other 6 25%

How do you determine calories for your PN?

N=24 n

Metabolic chart/Indirect calorimetry

4 17%

Range of 50-90% of RDA

5 21%

RDA with stress factors

1 4%

Age ranges: 1-7 y : 75-90 kcal 7-12 y : 60-75 kcal 12-18 y : 30-60 kcal

1 4%

Schofield equitation 3 12%

Dependent on PN prescription/volume

5 21%

60-75% calories of enteral KD composition

2 8%

Unknown 3 13%

65

What percentage of goal calories do you start?

N = 24 n

100% 0 0%

50-75% 14 58%

<50% 2 8%

Other 8 34%

If you cannot reach your estimated calorie needs at goal ratio, do you...

N = 23 n

Decrease diet ratio to increase

calories

10 44%

Maintain ratio and continue 13 56%

How much protein or amino acids do you start?

N= 24 n

0.5 g/kg or less 4 17%

0.6-1 g/kg 5 21%

1-1.2 g/kg 8 33%

More than 2 g/kg 7 29%

What is your goal for protein/amino acids?

N = 24 n

ASPEN/ESPEN guidelines 7 29%

WHO guidelines 2 8%

RDA guidelines 6 25%

Individually calculated 9 38%

When calculating a Ketogenic PN, and based on what your hospital pharmacy is able to

compound, what percentage of dextrose/glucose do you include in your PN?

N=24 n

0% dextrose solution 11 45%

Glucose 2.5% 2 8%

Depending on diet ratio 2 8%

Depending on carbohydrate content regular KD

3 13%

Glucose 1-2 % 2 8%

75-350 mg/L 1 5%

Unknown 3 13%

How many hours per day do you run your keto TPN?

N = 23 n

24 hours 18 79%

20 hours 1 4%

Intermittent 4 17%

66

Lipid Calculation Questions:

N=24 n

How do you start your lipids?

50% of goal n=6 1 g/kg n=7 2 g/kg n=5 3 g/kg n=1 Start with goal n=0 Other n=5

25% 29% 21% 4% 0% 21%

What is your goal for lipids?

ESPGHAN/ASPEN guidelines : n=4 3-4 g/kg n=17 Other n=2 Unknown n=1

17% 70% 8% 5%

How long do you run your lipids in 24 hours?

24 hours n=17 20 hours n=3 Intermittent n= 4

71% 12% 17%

How do you advance your lipids to goal?

1 - 1.9 g/kg/day n=13 2 - 4 g/kg/day n=2 Already started with goal n=1 Other n=7 Unknown n=1

54% 8% 4% 29% 5%

Do you calculate glycerin content from lipids as carbohydrates?

N=24 n

No 14 58%

Yes 10 42%

*If yes, calculate 22.5 g/L

What ratio do you reach when writing Ketogenic PN (on average)?

N= 24 n

4:1 3:1-3.9:1 2:1-2.9:1 Less than 2:1 Unknown

0 3 11 7 3

0% 13% 46% 29% 12%

Are your patients able to reach or maintain ketosis while on ketogenic TPN (on average)?

N = 22 n

100% of the time 4 18%

75-99% of the time 4 18%

50-74% of the time 6 27%

25-49% of the time 3 14%

<25% of the time 4 18%

Never 1 5%

67

Do you add a multivitamin?

N =24 n

Add a multivitamin Yes 20 83%

Sometimes 3 12%

Sometimes, depending on duration TPN 1 5%

How often do you check blood glucose?

N = 24 n

Every 4-6 hours 10 42%

Every 8-12 hours 2 8%

Never 0 0%

Once daily 1 4%

Other 11 46%

How often do you check beta-hydroxybutyrate levels?

N=24 n

Once daily 7 29%

2x weekly 2 8%

More than 2 x weekly 0 0%

More than once daily 3 13%

Other 12 50%

Additional Monitoring questions: (open ended):

Additional Laboratory measurements: (Besides glucose, beta-hydroxybutyrate and lipid profile)

-Blood gas -Electrolytes -liver/renal panel -Amylase, direct Billi -carnitine (acyl) -total protein/Albumin -Mg, Phos, Ca,Cu, HB (Se, Zn , vit.D )

Labs at start and frequency during TPN differs significantly between centers and is highly dependent on clinical situation and ICU protocol.

Summary of complications during ketogenic PN

Complication N=24 Incidence

Hyperlipidemia 17 71%

Insufficient ketosis 14 58%

Hypoglycemia 3 12%

Hyperketosis 3 12%

High Bilirubin 1 4%

Others: - no complications - pancreatitis - multi systemic organic failure

2 1 1 1

8% 4% 4% 4%

68

-general electrolyte abnormalities -instability of solution by Mg and Ca

1 4%

What is the maximum duration you will allow a patient to be on ketogenic PN?

N = 23 n

3 days or less 1 4%

No more than 1 week 3 13%

No restrictions 8 35%

Only stopped if lab values indicate the need to discontinue

11 48%

69

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