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Review Articles: Narrative Review Article

Perioperative Management of Children on Ketogenic Dietary Therapies

Conover, Zacherie R. MD*; Talai, Afsaneh MD; Klockau, Katherine S. PharmD; Ing, Richard J. MBBCh, FCA(SA)*; Chatterjee, Debnath MD, FAAP*

Author Information
doi: 10.1213/ANE.0000000000005018
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Abstract

Ketogenic diet therapy (KDT) is an established treatment for children with drug-resistant epilepsy and a variety of other metabolic and neurologic disorders, with evidence of its use dating back to the early 1920s.1 The basic principle of KDT is the induction and maintenance of ketosis, and there are different dietary strategies to achieve this. This metabolic state leads to an effective reduction of seizures, although the exact mechanism by which this occurs remains controversial.

Because KDTs are more commonly being used in epilepsy management, children on KDTs will be presenting to the operating room for a variety of surgical procedures. Pediatric anesthesiologists play a critical role in the safe perioperative management of these children; therefore, a thorough understanding of the basic principles of KDTs is both relevant and essential for the pediatric anesthesiologist. Children on KDTs presenting for invasive surgical procedures and general anesthesia are at an increased risk compared to the general population.2 The metabolic changes that are seen with acute illness or surgery can precipitate worsened acidosis or loss of ketosis, which can lead to significant adverse effects, including the exacerbation of seizures.2 Preoperative optimization and decisions regarding fasting times, choice of medications administered, and intraoperative volume replacement during the perioperative period have a direct impact on the outcomes of these patients. Unfortunately, there is a lack of evidence-based guidelines for the anesthetic management of children on KDTs. In this narrative review, we provide an overview of the historical background, clinical indications, contraindications, proposed anticonvulsant mechanisms, initiation, and monitoring of children on KDTs. Recommendations for the perioperative management of children on KDTs will be summarized.

BACKGROUND

For over 2500 years, starvation has been used to treat seizures. Fasting was recorded as a therapy for epilepsy as early as the Hippocratic era, with references in Biblical times.3 In 1911, Guelpa and Marie,4 a pair of Parisian physicians, reported the first modern use of starvation as a therapeutic option for epilepsy. Given the difficulty of maintaining fasting for prolonged periods of time, Wilder,1 in 1921, proposed a high-fat diet inducing ketonemia that had similar beneficial effects of fasting but without the need for prolonged fasting. KDT lost its popularity in the late 1930s with the discovery of new anticonvulsant therapies. However, it gained its popularity back again in the 1990s, and it has experienced a reemergence in recent years, especially in children with drug-resistant epilepsy.5

The 4 major types of KDTs include the classic ketogenic diet, the medium-chain triglyceride diet, the modified Atkins diet, and the low glycemic index treatment.3,6 The classic ketogenic diet is the strictest of the diets, where the fat source is primarily from long-chain triglycerides, whereas carbohydrate and protein intake is significantly restricted. The classic ketogenic diet is classified according to a ratio of fat to carbohydrate plus protein. The most common ratio is 4 g of fat to 1 g of carbohydrate plus protein (4:1), and 90% of calories are derived from fat. The medium-chain triglyceride diet is an alternative form of the classic ketogenic diet, where medium-chain triglycerides provided in an oil supplement are used as the primary fat source for 50%–70% of the calorie intake.6 Medium-chain triglycerides provide more ketones per kilocalories compared to long-chain triglycerides and are more efficiently absorbed. The modified Atkins diet is less restrictive and allows 10–20 g of carbohydrates daily, with no restrictions on protein, fluid, or calorie intake. The low glycemic index treatment is even less restrictive, allowing 40–60 g of carbohydrates daily, but it emphasizes the intake of carbohydrates with a glycemic index <50.6

Anticonvulsant Mechanisms of Ketogenic Dietary Therapies

Despite a century of use, the exact anticonvulsant mechanism of KDT remains unknown and is probably multifactorial.7,8 The role of ketone bodies, glucose restriction, fatty acids, and neurotransmitter systems will be discussed (Figure). Production of ketone bodies (β-hydroxybutyrate, acetone, and acetoacetate) by the liver is a hallmark feature of KDT, and measurement of β-hydroxybutyrate levels in the blood is often used as a clinical indicator of successful ketosis.7 However, there is no conclusive evidence for the direct anticonvulsant effects of ketone bodies.7 Optimal seizure protection lags days to weeks behind ketonemia, which occurs within hours of implementing the KDT, suggesting that adaptations to ketonemia rather than direct effects are responsible for the anticonvulsant nature of KDT. Another critical feature of KDT is calorie restriction (CR).9–11 It has been hypothesized that CR reduces cerebral glucose utilization and inhibits glycolysis, which limits neuronal excitability necessary for seizures. Further support for the role of CR and glycolysis inhibition is provided by experiments with 2-deoxy-d-glucose, which is a glucose analog that inhibits glycolysis. Two-deoxy-d-glucose has been shown to have anticonvulsant and antiepileptic properties in several experimental models by blocking the seizure-induced expression of brain-derived neurotrophic factor (BDNF) and its receptor, tyrosine receptor kinase B (TrkB).9–11 In addition, CR activates adenosine triphosphate (ATP)-sensitive potassium (KATP) channels throughout the central nervous system, both in neurons and glia, leading to membrane hyperpolarization and decreased seizures.11

Figure.
Figure.:
Proposed anticonvulsant mechanisms of ketogenic dietary therapies. ATP indicates adenosine triphosphate; BDNF, brain-derived neurotrophic factor; Ca2+, calcium; GABA, gamma amino butyric acid; K+, potassium; K2p, 2-pore domain potassium; KATP, ATP-sensitive potassium; Na+, sodium; PUFA, polyunsaturated fatty acids; ROS, reactive oxygen species; TCA, tricarboxylic acid. Adapted with permission from Bough and Rho.7

Elevations in the brain and serum levels of polyunsaturated fatty acids (PUFAs) such as docosahexaenoic acid, arachidonic acid, and eicosapentaenoic acid are commonly seen in KDTs.6 PUFAs directly limit neuronal excitability and dampen seizure activity by inhibiting voltage-gated sodium (Na+) and calcium (Ca2+) ion channel activity,12 activating 2-pore domain potassium (K2P) channels13 and enhancing the activity of the Na+/K+-ATPase pump. Acting indirectly, PUFAs also have a neuroprotective effect by inducing the expression of mitochondrial uncoupling proteins that decrease the production of reactive oxygen species.14 In addition, PUFAs induce a coordinated upregulation of oxidative phosphorylation, leading to enhanced energy reserves, stabilized synaptic function, and limited neuronal hyperexcitability.15

A role for neurotransmitter systems is increasingly being recognized in the anticonvulsant mechanism of KDTs.6 Norepinephrine levels in the hippocampus are increased by approximately 2-fold after KDT, and the increased noradrenergic signaling in the brain confers anticonvulsant activity.16 KDTs also significantly increase the levels of the inhibitory neurotransmitter γ-aminobutyric acid (GABA) and glutamine, which dampens hyperexcitability throughout the brain.6 Ketosis and decreased glucose in KDTs alter the equilibrium of the tricarboxylic acid cycle that decreases aspartate production and increases the availability of glutamate, which is the precursor for GABA synthesis through the glutamate decarboxylase reactions.16 It is likely that a combination of the above mechanisms contributes to the anticonvulsant effect of KDT.

Indications for Ketogenic Dietary Therapies

Epilepsy is the most common indication for the KDT in children. It is well known that the response to anticonvulsant medications reduces as a patient fails each additional medication trialed.17 For this reason, once a patient fails at least 2 appropriate anticonvulsant medications, nonpharmacological options are considered next. These include KDTs, epilepsy surgery, or placement of a vagal nerve stimulator. For patients who are not surgical candidates, KDT is often chosen as the next treatment option. Children with generalized seizures and those who respond with >50% seizure reduction within 3 months tend to remain on the diet longer. These patients are twice as likely to achieve therapeutic success, which is defined as >50% reduction in seizure frequency.18 There is growing evidence that KDTs should be considered earlier in the treatment of certain epilepsy syndromes given the significant reduction in seizures achievable by the use of the KDTs in those conditions6 (Table 1). Further, KDT is the primary treatment of choice in 2 conditions: glucose transporter type 1 deficiency syndrome (Glut1DS) and pyruvate dehydrogenase deficiency (PDHD).6 In both these conditions, ketones produced by the KDT provide an alternative source of energy for the brain that is otherwise affected due to the metabolic defect caused by the inborn error of metabolism.

Table 1. - Common Indications and Contraindications to the Use of KDTs
Epilepsy syndromes and conditions that are particularly responsive to KDTs
 Angelman syndrome
 Complex 1 mitochondrial disorders
 Dravet syndrome
 Epilepsy with myoclonic-atonic seizures (Doose syndrome)
 Glut1DS
 Febrile infection–related epilepsy syndrome
 Formula-fed (solely) children or infants
 Infantile spasms
 Ohtahara syndrome
 PDHD
 Super-refractory status epilepticus
 Tuberous sclerosis complex
Absolute contraindications to KDTs
 Carnitine deficiency (primary)
 Carnitine palmitoyltransferase I or II deficiency
 Carnitine translocase deficiency
 b-oxidation defects
 Medium-chain acyl dehydrogenase deficiency
 Long-chain acyl dehydrogenase deficiency
 Short-chain acyl dehydrogenase deficiency
 Long-chain 3-hydroxyacyl-CoA deficiency
 Medium-chain 3-hydroxyacyl-CoA deficiency
 Pyruvate carboxylase deficiency
 Porphyria
Relative contraindications to KDTs
 Inability to maintain adequate nutrition
 Surgical focus identified by neuroimaging and video-EEG monitoring
 Parent or caregiver noncompliance
 Prolonged/concurrent propofol administration (higher risk of propofol infusion syndrome)
Reproduced with permission from Kossoff et al.6
Abbreviations: CoA, coenzyme A; EEG, electroencephalography; Glut1DS, glucose transporter protein 1 deficiency syndrome; KDT, ketogenic dietary therapy; PDHD, pyruvate dehydrogenase deficiency.

While epilepsy is the most well studied and commonly used indication for KDTs, there is growing literature to support its use for other conditions. Several studies have shown improvement in the core behavioral features of patients with autism spectrum disorder.19 Recent literature has shown a reduction in both the frequency of hemiplegic attacks and epileptic seizures when using KDTs in patients with alternating hemiplegia of childhood, a channelopathy causing paroxysmal hemiplegia as well as epilepsy.20–22 There is growing evidence of the benefits of KDTs in animal models of Parkinson’s disease, amyotrophic lateral sclerosis, and multiple sclerosis.23,24 Several small studies have been published evaluating KDTs in the treatment of various types of oncologic patients with mixed results. Larger well-designed studies are still needed to show the efficacy of the KDTs in patients with cancer.25–28

Contraindications to Ketogenic Dietary Therapies

Given that KDTs involve the use of fat in place of carbohydrates as a source of energy, patients with disorders in fat metabolism are at an increased risk for life-threatening catabolic crisis (ie, coma, death), if placed on a KDT. Before initiating the KDT, the patient should be screened for inborn errors of metabolism that affect the transport or oxidation of long-chain fatty acids.6 Porphyrias are also another contraindication to the initiation of KDTs. The absolute and relative contraindications for initiating KDT are listed in Table 1. KDTs can cause patients to lose weight; therefore, if a child is unable to maintain adequate nutrition on the KDT, this would be a reason for discontinuation. If a surgical focus for seizures is identified, surgery is prioritized because this can provide a better chance for a cure. KDTs also require strict adherence to a certain diet, and if parents are unable to comply with this regimen, this would raise hesitation in the initiation of the diet or may prompt discontinuation.

Implementation of Ketogenic Dietary Therapies

Preinitiation.

Before starting the KDT, patients are seen in the clinic for a preinitiation evaluation and education on the diet. A detailed history, physical examination, and laboratory investigations are performed to rule out metabolic disorders that are contraindications to KDTs (Table 1) as well as to evaluate for complicating comorbidities. These comorbidities include nephrolithiasis, hypercholesterolemia, poor nutrition, gastroesophageal reflux, constipation, cardiomyopathy, and chronic metabolic acidosis. While not contraindications to KDTs, these comorbidities do require additional considerations and adjustments when initiating the diet. Establishing a patient’s baseline nutritional status is also important before initiating the diet so that changes can be accurately monitored. Recommended laboratory investigations before initiating KDT include complete blood count, complete metabolic profile, fasting lipid profile, serum acylcarnitine profile, vitamin D level, and urinalysis.6 While larger institutions complete many of these laboratory investigations, a minimum required set of laboratory investigations have also been recommended for developing countries with limited resources.29 Parental teaching, psychosocial evaluation, and setting expectations are also vital components of the preinitiation visit.6

Initiation.

The classic ketogenic diet is most often started during inpatient admission to allow for stricter clinical and laboratory monitoring as ketosis is reached much faster; therefore, the risk of metabolic acidosis is higher.6 Further, the classic ketogenic diet requires a more rigorous weighing of food and the teaching of caregivers. The remaining KDTs are typically started in the outpatient setting. Historically, the classic ketogenic diet was started after a 12- to 24-hour fast.30 However, many centers have moved away from fasting and instead begin with a full-calorie diet and a gradual daily increase in the fat to protein/carbohydrate ratio, until the typical goal ratio is reached. By omitting the fast, immediate morbidity from acute acidosis is reduced while ketogenesis and the effect of the KDT are not reduced.

Dietary Options.

The route of KDT administration is based on oral intake versus gastrostomy tube status, patient/caregiver preference, and patient tolerance. KDTs can be administered as a liquid formula, blended formula made from pureed foods, or typical food items.

Monitoring.

A dietician and neurologist should monitor the efficacy of the diet at regular intervals. Monitoring parameters at each visit should include a comprehensive nutritional assessment (caloric intake, height, and weight) and repeating the laboratory investigations.6 It is recommended that patients test their urine ketones at home several times per week, especially at the start of the diet, to establish the patient’s baseline and to ensure that the patient is maintaining ketosis. Once the patient has maintained stability on the diet, urine ketones can be checked as needed, such as in cases of seizure exacerbation.

Duration.

The diet is typically recommended for a minimum of 3 months and a maximum of 2 years.6 The efficacy of the diet is usually apparent in the first 1–3 months. The duration of treatment, however, can be individualized based on the disorder being treated, tolerability of the diet, and physician or patient/parent preference. Discontinuation of the diet is typically done slowly over several weeks to months. If needed, the diet can be abruptly stopped in emergent situations, with the understanding that seizures may be exacerbated. Notably, there is evidence for continued benefit from the KDTs even after weaning off of the diet.31

Adverse Effects.

Gastrointestinal symptoms such as constipation, abdominal pain, and diarrhea are the most common side effects, which are generally managed symptomatically.6 Hyperlipidemia is the next most common adverse effect and is monitored closely. Most cases of elevated lipids occur within the first few months of treatment initiation and typically resolve by 12 months. Despite this risk of hyperlipidemia, studies have shown no impact on cardiovascular health in both pediatric and adult patients on KDTs.32–34 Other adverse effects include hypoglycemia, growth failure, severe metabolic acidosis, nephrolithiasis, pancreatitis, liver transaminitis, and osteopenia. A mild chronic metabolic acidosis is not uncommon in patients on KDTs. However, severe metabolic acidosis can rarely occur, especially in the setting of illness or dehydration, and should be treated promptly. Nephrolithiasis can be seen in 3%–7% of patients on KDTs. This increased risk is due to the secondary effects of chronic metabolic acidosis, which causes increased crystallization of uric acid in the urine along with increased bone demineralization leading to increased calcium in the urine. Many institutions empirically start these patients on oral citrate, which reduces the risk of kidney stones by alkalinizing the urine and solubilizing urine calcium. Cardiac abnormalities are a rare but serious adverse effect of the KDTs. There have been cases of cardiomyopathy and prolonged corrected QT interval reported in the literature, with some but not all cases being related to selenium deficiency.35–37 There is currently no recommendation for routine screening for cardiac abnormalities, unless clinically suggested.

Ketogenic Dietary Therapies and Anesthesia

With the resurgence of interest in KDTs in children, pediatric anesthesiologists will increasingly be caring for these patients as they present for a variety of surgical or medical procedures. Multiple case reports and case series have been published discussing the anesthetic management of children on KDTs.2,38–41 In 1982, Hinton et al38 described 3 children on KDT who underwent short procedures under general anesthesia without any complications. In 2000, McNeely39 described the uneventful perioperative management of a patient on KDT undergoing surgical correction of thoracolumbar scoliosis. In 2002, Valencia et al41 described 9 patients on KDT undergoing general anesthesia for a total of 24 surgical procedures with stable serum glucose levels despite prolonged fasting and without increased postoperative complications. In 2006, Ichikawa et al40 described the perioperative management of a child on KDT undergoing treatment for dental caries. The largest retrospective review to date was published in 2016 by Soysal et al,2 which included 24 patients who underwent 33 procedures ranging from esophagogastroduodenoscopy to craniotomy. Two patients in this group experienced worsened seizures postoperatively, and 1 patient had severe metabolic acidosis requiring bicarbonate administration. All these publications emphasize the importance of continuing ketosis, avoiding medications with high carbohydrate content and monitoring the patient’s serum glucose, electrolytes, and pH throughout the perioperative period.

A comprehensive preoperative evaluation is warranted before any anesthetic encounter. Ideally, the patient’s neurologist or dietitian should assess the patient’s global nutritional status, calorie intake, efficacy of the KDT, and monitor for common adverse effects, as listed previously. Close communication with the neurology team managing the patient’s KDT is critical. Preoperative laboratory testing should include complete blood cell count, comprehensive metabolic profile including serum electrolytes, bicarbonate, calcium, magnesium, albumin, and prealbumin levels. Additional testing such as electrocardiogram, lipid profile, liver function tests, and urinalysis is dictated by the presence of other side effects and comorbidities. Prolonged preoperative fasting increases the risk of hypoglycemia and must be avoided. Preoperatively, glucose-containing electrolyte solutions and intravenous fluids must be avoided.

The high-fat, low carbohydrate nature of KDTs triggers the body to use fat instead of carbohydrates to produce energy. However, if carbohydrates are administered, the body favors its use over fat to produce energy; therefore, ketosis is lost. Unfortunately, many oral and parental medications that anesthesiologists routinely administer contain high concentrations of carbohydrates that would likely result in a loss of ketosis and, therefore, increase the risk of postoperative seizures. The anesthesiologist must carefully consider the carbohydrate content of every medication administered, which is a potentially cumbersome task. For the pediatric anesthesiologist, it is worth noting that most oral suspensions (ie, midazolam, ibuprofen, and acetaminophen) contain significant amounts of carbohydrate.42,43Tables 2–4 list the carbohydrate content of medications commonly used by anesthesiologists in the perioperative period. Based on the carbohydrate ingredients identified in the drug package insert, medications are categorized as those that can be used per routine (Table 2), medications that should be used with caution due to the unknown clinical significance of carbohydrates listed in the package insert (Table 3), and medications that should be avoided as much as possible in children on KDTs (Table 4). While reviewing the package insert of medications, carbohydrate ingredients that may contribute to the carbohydrate count includes sugars such as monosaccharides (fructose, glucose, dextrose), disaccharides (sucrose, lactose), oligosaccharides (maltodextrin), and polysaccharides (starch). Gluconate ingredients may also be considered (calcium gluconate, sodium gluconate), although it is unclear if the intravenous administration of gluconate results in a clinically significant rise in plasma glucose levels. Other ingredients to consider include the oral intake of sugar alcohols such as mannitol, xylitol, sorbitol, glycerol, and glycol (including propylene glycol which has the general structure of a carbohydrate and should be included in carbohydrate declarations). It is unclear whether the intravenous administration of sugar alcohols (mannitol) results in an appreciable increase in plasma glucose levels.123

When reviewing the carbohydrate content of a medication, it is also essential to know the manufacturer of the generic product because inactive ingredients may differ among manufacturers of generic medications. Manufacturers of generic medications are not required to publish the amount of each inactive ingredient in their formulation because this is considered proprietary information.124 When selecting the more appropriate formulation of a drug to administer, oral tablets and capsules are considered to have lower carbohydrate content than the oral suspension or chewable tablet. Liquid medications and chewable tablets are often formulated with flavoring agents and sweeteners. Carbohydrates from intravenous medications can also be the cause for insufficient ketosis from elevated glucose levels and should be reviewed before administration in the patient on KDT.125 In addition, the anesthesiologist should recognize that transfusion of blood products (including whole blood, packed red blood cells, fresh frozen plasma, and cryoprecipitate) might contain significant and variable amounts of carbohydrate both from the donor’s plasma and preservative solutions.126 While blood product administration might lead to a loss of ketosis, transfusion should not be withheld on this basis alone.

Intraoperatively, frequent monitoring (every 2–3 hours) of the patient’s serum pH, glucose, bicarbonate, and electrolytes is critical. It should be recognized that serum glucose levels of patients on KDT are usually in the range of 50–80 mg/dL127 and should be treated only for levels <40 mg/dL or if the patient is symptomatic. Due to the likelihood of a baseline metabolic acidosis, significant surgical stress and volume losses may lead to severe acidosis and increased postoperative seizure activity.41 Therefore, adequate volume resuscitation is an important consideration. The safe use of both normal saline and lactated Ringer’s solution has been described in previous anesthesia case series, and there is no consensus on the ideal maintenance intravenous fluid.2,39–41 Some authors consider lactated Ringer’s solution to be relatively contraindicated secondary to the theoretical risk of losing ketosis through gluconeogenesis and, therefore, prefer to use normal saline.2 However, large volumes of normal saline administration should be avoided due to the risk of developing a hyperchloremic metabolic acidosis.2 In the event of significant acidosis, treatment with sodium bicarbonate can be considered.41 Drugs that cause hyperglycemia such as steroids may alter the ketogenic state. Seventeen of the 24 patients in the case series published by Soysal et al2 received dexamethasone for postoperative nausea and vomiting (PONV) prophylaxis and only one of them had seizures postoperatively. In a randomized, double-blinded, placebo-controlled investigation examining the effects of the administration of 2 standard doses of dexamethasone (4 and 8 mg) on perioperative blood glucose concentrations in adult patients undergoing gynecologic surgery, the incidence of perioperative hyperglycemic episodes (blood glucose measurements >180 mg/dL) did not differ among the study groups.128 Although it is unlikely that a single, low-dose dexamethasone administration will lead to the loss of a ketogenic state, other options for PONV prophylaxis should be considered in patients on KDT.

While propofol may be safe for anesthetic induction, the use of high doses of propofol infusion for long periods of time is not recommended in patients on KDT.2 This is secondary to concerns of developing propofol infusion syndrome (PRIS), which is characterized by a high anion gap metabolic acidosis, rhabdomyolysis, refractory hypotension, and multisystem organ failure.129 There is an association between PRIS and the use of propofol infusions at doses higher than 4 mg/kg/h for >48 hours.130 PRIS has been implicated as the cause of multisystem organ failure and death in a 10-year-old boy on KDT for whom a propofol infusion was used for the treatment of refractory status epilepticus.131 Recommendations for the anesthetic management of children on KDTs are summarized in Table 5.

Table 2. - Commonly Used Perioperative Medications That Usually Do Not Contain any Carbohydrates and Can be Used per Routine in Children on Ketogenic Dietary Therapies
Medication Concentration Manufacturer
Sedatives/hypnotics
 Clonidine injection44 100 and 500 μg/mL X-gen Pharmaceuticals
 Dexmedetomidine injection45,46 100 μg/mL Intas Pharmaceuticals
4 μg/mL Baxter
 Ketamine injection47 50 and 100 mg/mL West-Ward
 Midazolam injection48 5 mg/mL Fresenius Kabi
Analgesics
 Acetaminophen suppository49 650 mg Perrigo
 Fentanyl injection50 50 μg/mL Hospira Inc
 Hydromorphone injection51,52 10 mg/mL Teva Parenteral Medications
2 mg/mL Hospira, Inc
 Ketorolac injection53 15 mg/mL Fresenius Kabi
 Morphine injection54 1 and 10 mg/mL West-Ward
 Remifentanil powder55 1, 2, and 5 mg Fresenius Kabi
 Sufentanil injection56 50 μg/mL Taylor Pharmaceuticals
Muscle relaxants
 Atracurium injection57 10 mg/mL Sagent Pharmaceuticals
 Cisatracurium injection58 2 mg/mL AbbVie Inc
 Pancuronium injection59 1 mg/mL Hospira, Inc
 Rocuronium injection60 10 mg/mL Fresenius Kabi
 Succinylcholine injection61 20 mg/mL Hospira, Inc
Local anesthetics
 Bupivacaine injection62 0.25%, 0.5% Aurobindo Pharma
 Chloroprocaine injection63 1%, 2%, 3% West-Ward
 Lidocaine injection64 1% Fresenius Kabi
 Ropivacaine injection65 0.2%, 0.5% Fresenius Kabi
Miscellaneous
 Albuterol inhalation solution66 0.083% Nephron SC Inc
 Diphenhydramine injection67 50 mg/mL West-Ward
 Neostigmine injection68 1 mg/mL West-Ward
 Ondansetron injection69 2 mg/mL West-Ward
 Sugammadex injection70 200 mg/2 mL Merck Sharp & Dohm Corp
Cardiac medications
 Aminocaproic acid injection71 250 mg/mL American Regent, Inc
 Atropine injection72 0.4 mg/mL American Regent, Inc
 Calcium chloride injection73 100 mg/mL Hospira, Inc
 Dobutamine injection74 12.5 mg/mL Hospira, Inc
 Dopamine injection75 40 mg/mL Hospira, Inc
 Ephedrine injection76 50 mg/mL Akorn
 Epinephrine injection77 1 mg/mL PF BPI Labs, LLC
 Esmolol injection78,79 10 mg/mL Baxter
100 mg/mL Fresenius Kabi
 Glycopyrrolate injection80 0.4 mg/2 mL Somerset Therapeutics, LLC
 Heparin injection81 1000 U/mL Fresenius Kabi
 Nitroprusside injection82 25 mg/mL Sagent Pharmaceuticals
 Phenylephrine injection83 10 mg/mL Fresenius Kabi
 Protamine injection84 10 mg/mL Fresenius Kabi
Fluids
 Albumin 5%85 250 mL Grifols USA
 Lactated Ringer’s solution86 1000 mL Baxter
 Normal saline87 1000 mL Baxter
Antibiotics
 Ampicillin powder88 1 g Sandoz, Inc
 Cefazolin powder89 1 g West-Ward
 Cefoxitin powder90 1 g Sagent Pharmaceuticals
 Clindamycin injection91 150 mg/mL Mylan

Table 3. - Carbohydrate Content of Commonly Used Perioperative Medications That Should be Used With Caution in Children on Ketogenic Dietary Therapies
Medication Concentration Manufacturer Carbohydrate Content
Sedatives/hypnotics
 Etomidate injection92 2 mg/mL West-Ward Propylene glycol 35% (v/v)
 Propofol injection93 10 mg/mL Fresenius Kabi Glycerol: 22.5 mg/mL
Analgesics
 Acetaminophen injection94 10 mg/mL Mallinckrodt Mannitol: 3.85 g/100 mL
Muscle relaxants
 Vecuronium powder for reconstitution95 1 mg/mL Aurobindo Pharma Mannitol: 97 mg/10 mL
Miscellaneous
 Dexamethasone injection96 4 mg/mL Mylan May increase blood glucose levels
 Mannitol injection97 20 g/100 mL Baxter Mannitol: 20 g/100 mL
 Calcium gluconate injection98 100 mg/mL Fresenius Kabi Calcium gluconate: 98 mg/mL
 Nitroglycerin injection99 5 mg/mL American Regent, Inc Propylene glycol 30%
Alcohol 30% (v/v)
Fluids
 Plasmalyte100 1000 mL Baxter Sodium gluconate: 502 mg/100 mL
Abbreviation: v/v, volume per volume.

Table 4. - Carbohydrate Content of Commonly Used Perioperative Medications That Should be Avoided in Children on Ketogenic Dietary Therapies
Medication Concentration Manufacturer Carbohydrate Content
Sedatives/hypnotics
 Midazolam oral syrup101 2 mg/mL Roxane Laboratories Glycerin
Sorbitol
Analgesics
 Acetaminophen tablet102 325 mg Johnson and Johnson Propylene glycol, sodium starch glycolate
 Acetaminophen chew tab103 80 mg Major Pharmaceuticals Mannitol, sucralose, dextrose monohydrate
 Acetaminophen oral suspension104 160 mg/mL Johnson and Johnson Glycerin, sorbitol, high fructose corn syrup, sucralose
 Gabapentin oral solution105 50 mg/mL Hi-Tech Pharmacal Xylitol: 1.75 g/5 mL
Glycerin: 1.4 g/5 mL
 Gabapentin oral capsules106 100, 300, and 400 mg Amneal Pharmaceuticals Starch (corn)
 Hydromorphone tablet107 2 mg Lannett Company, Inc Lactose
 Ibuprofen oral suspension108 100 mg/5 mL Johnson and Johnson Glycerin, sucrose, pregelatinized starch
 Ibuprofen tablet109 200 mg Major Pharmaceuticals Corn starch, lactose, polydextrose
 Morphine oral solution110 2 mg/mL West-Ward Sorbitol, glycerin
 Oxycodone oral tablet111 5 mg KVK-Tech, Inc Starch, corn, lactose, sodium starch glycolate
 Oxycodone oral solution112 1 mg/mL Pharmaceutical Associates Sorbitol: 10.5%/5 mL
Miscellaneous
 Ondansetron oral solution113 4 mg/5 mL Amneal Pharmaceuticals Glycerin
 Ondansetron ODT114 4 mg Glenmark Pharmaceuticals Mannitol
 Ondansetron tablet114 4 mg Glenmark Pharmaceuticals Starch (corn)
 Oxymetazoline nasal spray115 0.05% Bayer Propylene glycol
Polyethylene glycol
Cardiac medications
 Dopamine injection116 1.6 mg/mL Hospira, Inc Dextrose: 5 g/100 mL
 Labetalol injection117 5 mg/mL Hospira, Inc Dextrose: 45 mg/mL
 Milrinone injection118 200 μg/mL Hikma Farmaceutica Dextrose: 49.4 mg/mL
 Milrinone injection119 1 mg/mL Hikma Farmaceutica Dextrose: 47 mg/mL
 Cefazolin in dextrose injection120 20 mg/mL Baxter Dextrose: 2 g/50 mL
 Clindamycin in 5% dextrose injection121 18 mg/mL Sandoz, Inc Dextrose: 50 mg/mL
 Vancomycin in dextrose injection122 5 mg/mL Baxter Dextrose: 5 g/100 mL
Abbreviation: ODT, oral disintegrating tablet.

Table 5. - Recommendations for the Perioperative Management of Children on KDTs
Preoperative preparation
 1. Consult with neurology team managing the patient’s KDT regarding the patient’s nutritional status, efficacy of KDT, concurrent anticonvulsant medications, and presence of side effects from KDT
 2. Preoperative laboratory investigations should include CBC, comprehensive metabolic profile including serum electrolytes, calcium, magnesium, albumin, and prealbumin
 3. Avoid prolonged fasting secondary to the risk of hypoglycaemia
 4. Avoid preoperative administration of carbohydrate-containing electrolyte solutions and intravenous fluids
 5. Measure preoperative fasting serum glucose on the day of surgery
 6. Avoid preoperative sedation with oral midazolam solution secondary to high carbohydrate content. Alternatives for preoperative sedation include intranasal midazolam or dexmedetomidine, if necessary.
Intraoperative management
 1. Avoid carbohydrate-containing medications
 2. Avoid using high doses of propofol infusions for long periods of time secondary to the risk of PRIS
 3. Use isotonic crystalloid solutions (NS or LR) for volume replacement. Some authors consider LR to be relatively contraindicated and prefer to use NS. Avoid using large volumes of NS secondary to the risks of hyperchloremic metabolic acidosis
 4. For major surgical procedures or those lasting >3 h, frequently monitor serum pH, glucose, electrolytes, and bicarbonate levels
 5. Do not overcorrect hypoglycemia (start with dextrose 0.25 g/kg for serum glucose <40 mg/dL)
Postoperative management
 1. Inpatient monitoring versus same-day discharge as clinically indicated
 2. Advance diet as surgically appropriate, to resume KDT. Consider measuring serum or urine ketone levels
Abbreviations: CBC, complete blood cell count; KDT, ketogenic dietary therapy; LR, lactated Ringer’s solution; NS, normal saline; PRIS, propofol infusion syndrome.

In addition to the effects of medications and general anesthesia on a patient on KDT, it is also important to consider how ketosis affects the general anesthetic. Ari et al132 recently demonstrated that increased blood ketone levels from a ketogenic diet or from exogenous ketone supplements in a rat model delayed the onset of inhalational induction with isoflurane. The authors postulate that nutritional ketosis may cause a delay in the onset of isoflurane-induced immobility by increasing adenosine levels and its effects in different brain areas are implicated in sleep-wake regulation. The effects of ketosis on the speed of inhalational induction in children require further examination. It is currently unknown if ketosis affects the therapeutic effects of other drug classes, such as opioids or benzodiazepines. Another area for clinical research is whether achieving ketosis enhances neuroprotection from exposure to harmful toxic gases in first responders or military personnel.

CONCLUSIONS

As KDTs are increasingly being used as a treatment modality for children with drug-resistant epilepsy and other metabolic and neurologic disorders, pediatric anesthesiologists should be familiar with the basic principles of this therapy as well as its implications on perioperative care. Major anesthetic considerations include a comprehensive preanesthetic evaluation, continuation of ketosis, avoiding medications with high carbohydrate content, and monitoring the patient’s serum pH, glucose, and electrolytes throughout the perioperative period.

DISCLOSURES

Name: Zacherie R. Conover, MD.

Contribution: This author helped write and revise the manuscript.

Name: Afsaneh Talai, MD.

Contribution: This author helped write and revise the manuscript.

Name: Katherine S. Klockau, PharmD.

Contribution: This author helped write and revise the manuscript.

Name: Richard J. Ing, MBBCh, FCA(SA).

Contribution: This author helped write and revise the manuscript.

Name: Debnath Chatterjee, MD, FAAP.

Contribution: This author helped write and revise the manuscript.

This manuscript was handled by: James A. DiNardo, MD, FAAP.

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