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Coronavirus disease (COVID-2019) is a devastating viral illness that originated in Wuhan China in late 2019 and there are nearly 2 million confirmed cases. The mortality rate is approximately 5% of reported cases and over half of patients that require mechanical ventilation for respiratory failure. As the disease continues to spread, strategies for reducing duration of ventilator support in patients with COVID-19 could significantly reduce morbidity and mortality of these individuals and future patients requiring this severely limited life-saving resource. Methods to improve gas exchange and to reduce the inflammatory response in COVID-19 are desperately needed to save lives.
The ketogenic diet is a high fat, low carbohydrate, adequate-protein diet that promotes metabolic ketosis (ketone body production) through hepatic metabolism of fatty acids. High fat, low carbohydrate diets have been shown to reduce duration of ventilator support and partial pressure carbon dioxide in patients with acute respiratory failure. In addition, metabolic ketosis reduces systemic inflammation. This mechanism could be leveraged to halt the cytokine storm characteristic of COVID-19 infection.
The hypothesis of this study is that the administration of a ketogenic diet will improve gas exchange, reduce inflammation, and duration of mechanical ventilation. The plan is to enroll 15 intubated patients with COVID 19 infection and administer a 4:1 ketogenic formula during their intubation.
Coronavirus disease (COVID-2019) is a devastating viral illness that originated in Wuhan China in late 2019. The number of confirmed cases worldwide has nearly reached 2 million and more than 125,000 people have died. Early studies from Wuhan reported a mortality rate of 2-3% with lower rates in surrounding provinces as the disease spread (closer to 0.7% of confirmed cases). One hypothesized cause for the higher mortality rate in Wuhan compared to surrounding regions was the rapid "surge" of COVID-19 infections before the disease was identified and social distancing implemented. Critically ill patients developed acute respiratory distress syndrome with inflammatory pulmonary edema and life-threatening hypoxemia requiring mechanical ventilation. This resulted in a significant strain on health-care resources such as availability of mechanical ventilators to treat patients with acute respiratory failure. As the disease spreads worldwide, strategies for reducing duration of ventilator support in patients with COVID-19 could significantly reduce morbidity and mortality of these individuals and future patients requiring this severely limited life-saving resource.
Alterations in macronutrient composition may be leveraged to improve ventilation and inflammation in COVID-19 patients. The ketogenic diet is a high fat, low carbohydrate, adequate protein diet that promotes ketone body production through hepatic metabolism of fatty acids. High fat, low carbohydrate diets have been shown to reduce duration of ventilator support and partial pressure carbon dioxide in patients with acute respiratory failure. Switching from glucose to fat oxidation lowers the respiratory quotient, thereby reducing the amount of carbon dioxide produced. This reduces ventilator demands and may improve oxygenation by lowering alveolar carbon dioxide levels, ultimately reducing time on mechanical ventilation. A study published in 1989 compared 10 participants intubated for acute respiratory failure and randomized to a high-fat, low carbohydrate diet and 10 participants receiving a standard isocaloric, isonitrogenous diet and showed a decrease in the partial pressure of carbon dioxide of 16% in the ketogenic diet group compared to a 4% increase in the standard diet group (p=0.003). The patients in the high-fat diet group had a mean of 62 fewer hours on a ventilator (p = 0.006) compared to the control group.
The high-fat diet used in the study had a ratio of 1.2:1 fat to protein and carbohydrate combined in grams. The ketogenic diet, which has been used safely and effectively in patients with chronic epilepsy for nearly one century and more recently in critically ill, intubated patients for the management of refractory and super-refractory status epilepticus has a 4:1 ratio (90% fat kilocalories). While a 1:1 ratio diet can produce a state of mild metabolic ketosis (typically ~ 1 mmol/L of the ketone body betahydroxybutyrate, measured in serum), a higher 4:1 ratio ketogenic diet can produce higher ketone body betahydroxybutyrate levels and more rapidly (up to 2 mmol/L within 24 hours of initiation). One study of obese patients treated with ketogenic diet reported that increases in ketone body production correlated with a lower partial pressure of carbon dioxide levels. A more recent study showed that patients with refractory epilepsy had a reduction in the respiratory quotient and increased fatty acid oxidation without a change in the respiratory energy expenditure with chronic use of the ketogenic diet. These findings were replicated in healthy subjects on ketogenic diet compared to a control group and patients on a ketogenic diet also had a significant reduction in carbon dioxide output and partial pressure of carbon dioxide. The authors concluded that a ketogenic diet may decrease carbon dioxide body stores and that use of a ketogenic diet may be beneficial for patients with respiratory failure. Even in patients without hypercapnia (primarily hypoxic respiratory failure), lowering carbon dioxide production permits lowering tidal volumes - a cornerstone of acute respiratory distress syndrome management.
In addition to reducing the partial pressure of carbon dioxide, metabolic ketosis reduces systemic inflammation. This mechanism could be leveraged to halt the cytokine storm characteristic of COVID-19 infection. Several studies provide evidence that pro-inflammatory cytokine production is significantly reduced in animals fed a ketogenic diet in a variety of disease models. In a rodent model of Parkinson's disease, mice were found to have significantly decreased levels of pro-inflammatory, macrophage secreted cytokines interleukin-1β, interleukin-6, and Tumor necrosis factor-alpha after 1 week of treatment with a ketogenic diet. Likewise, rats pretreated with a ketogenic diet prior to injection with lipopolysaccharide to induce fever did not experience an increase in body temperature or interleukin-1β, while significant increases were seen in control animals not pretreated with a ketogenic diet. In a mouse model of NLRP3-mediated diseases as well as human monocytes, the ketone body beta-hydroxybutyrate inhibited the NLRP3 inflammasome-mediated production of interleukin-1β and interleukin-18. These findings have been replicated in several recent animal studies and preliminary studies in humans. The hypothesis of this study is that through induction of metabolic ketosis combined with carbohydrate restriction, a ketogenic diet is protective against the cytokine storm in COVID-19. With its carbon dioxide-lowering and anti-inflammatory properties, a ketogenic diet may become an important component of the acute respiratory distress syndrome arsenal with immediate relevance to the current COVID-19 pandemic.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Intubated patients with COVID-19 on a ketogenic diet only | Experimental | 4:1 ketogenic diet formula |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Ketogenic diet | Dietary Supplement | 4:1 ratio enteral ketogenic formula within 48 hours of intubation |
|
| Measure | Description | Time Frame |
|---|---|---|
| Change in the partial pressure of carbon dioxide (PaCO2) | PaCO2 is the partial pressure of carbon dioxide Units: millimeters of mercury | Daily until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days |
| Measure | Description | Time Frame |
|---|---|---|
| Change in minute ventilation | Minute ventilation is the product of respiratory rate and tidal volume. Units: Liter per minute | every 6 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days |
| Change in respiratory system compliance |
| Measure | Description | Time Frame |
|---|---|---|
| Change in total blood cholesterol level | Units: milligram/deciliter | At baseline and every 24 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days |
| Change in blood low-density lipoprotein level |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Mackenzie Cervenka, MD | Johns Hopkins University | Principal Investigator |
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| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 32109372 | Background | Ji Y, Ma Z, Peppelenbosch MP, Pan Q. Potential association between COVID-19 mortality and health-care resource availability. Lancet Glob Health. 2020 Apr;8(4):e480. doi: 10.1016/S2214-109X(20)30068-1. Epub 2020 Feb 25. No abstract available. | |
| 2504796 | Background | al-Saady NM, Blackmore CM, Bennett ED. High fat, low carbohydrate, enteral feeding lowers PaCO2 and reduces the period of ventilation in artificially ventilated patients. Intensive Care Med. 1989;15(5):290-5. doi: 10.1007/BF00263863. |
| Label | URL |
|---|---|
| Severe Outcomes Among Patients with Coronavirus Disease 2019 (COVID-19) - United States, February 12-March 16, 2020 | View source |
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| ID | Term |
|---|---|
| D000086382 | COVID-19 |
| D018352 | Coronavirus Infections |
| ID | Term |
|---|---|
| D011024 | Pneumonia, Viral |
| D011014 | Pneumonia |
| D012141 | Respiratory Tract Infections |
| D007239 | Infections |
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| ID | Term |
|---|---|
| D055423 | Diet, Ketogenic |
| D059039 | Standard of Care |
| ID | Term |
|---|---|
| D050528 | Diet, Carbohydrate-Restricted |
| D004035 | Diet Therapy |
| D044623 | Nutrition Therapy |
| D013812 | Therapeutics |
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This is a single-center, open-label, clinical trial designed to determine whether a ketogenic diet improves gas exchange and reduces ventilator requirements in patients with coronavirus disease intubated for respiratory failure. The study team will prospectively enroll 15 intubated patients with COVID-19 infection and administer a 4:1 ratio enteral ketogenic formula within 48 hours of intubation. This study will compare outcomes to a retrospective cohort of intubated patients with COVID-19 who did not receive ketogenic diet. As other clinical trials begin, co-administration of other therapies as well as standard care treatments will be recorded. In addition, the study will compare clinical outcomes with patients receiving exclusively standard clinical care.
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| standard of care | Other | standard of care/supportive therapy |
|
Respiratory system compliance measures the extent to which the lungs will expand. In a ventilated patient, compliance can be measured by dividing the delivered tidal volume by the [plateau pressure minus the total peep]. Units: liter/centimeter of water |
| every 6 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days |
| Change in driving pressure | Driving pressure is a measure of the strain applied to the respiratory system and the risk of ventilator-induced lung injuries Driving pressure = Plateau pressure - Total Positive end-expiratory pressure (PEEP) Units: centimeter of water | every 6 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days |
| Change in ventilator synchrony | Ventilator synchrony is the match between the patient's neural inspiratory time and the ventilator insufflation time | every 6 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days |
| Change in mean arterial pressure | Mean arterial pressure is the average pressure in a patient's arteries during one cardiac cycle. Mean arterial pressure = diastolic blood pressure +[1/3(systolic blood pressure - diastolic blood pressure)] Units: millimeter of mercury | every 6 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days |
| Change in the fraction of inspired oxygen percentage of oxygen (FiO2) | FiO2: Fraction of Inspired Oxygen Percentage of oxygen in the air mixture that is delivered to the patient. Units: % | every 6 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days |
| Change in the partial pressure of carbon dioxide (PaO2) to the fraction of inspired oxygen percentage of oxygen (FiO2) ratio | PaO2/FiO2 ratio is the ratio of arterial oxygen partial pressure (PaO2) to fractional inspired oxygen. Units: millimeter of mercury | every 6 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days |
| Change in hydrogen ion activity (pH) | pH measures hydrogen ion activity. It is a conventional part of every arterial blood gas determination pH: no units. | every 6 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days |
| Change in Bicarbonate (HCO3) | Bicarbonate is a conventional part of every arterial blood gas determination Units: milliequivalents/Liter | every 6 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days |
| Change in red blood cell count | Red blood cell count measure anemia or hypoglycemia. Units: cells per liter | every 6 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days |
| Change in white blood cell count | White blood cell count evaluates leukopenia or leukocytosis. Units: cells/liter | every 6 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days |
| Change in white cell differential | White cell differential shows the amount of neutrophils, lymphocytes, basophils, eosinophils and may give some clue of the type of infection. Units: % | every 6 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days |
| Change in hemoglobin levels | Hemoglobin is an indirect way to measure red blood cells. Units: gram/deciliter | every 6 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days |
| Change in hematocrit | Hematocrit measures the volume percentage of red blood cells in blood. Units: % | every 6 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days |
| Change in mean cell volume | Mean cell volume is a measure of the average volume of a red blood corpuscle. Units: femtoliters | every 6 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days |
| Change in mean cell hemoglobin | Mean cell hemoglobin is the average mass of hemoglobin per red blood cell in a sample of blood. Units: picograms | every 6 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days |
| Change in mean cell hemoglobin concentration | Mean cell hemoglobin concentration is the average concentration of hemoglobin in a given volume of blood. Units: % | every 6 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days |
| Change in platelet count | Platelet count measures the number of platelets in the blood and determines thrombocytopenia or thrombocytosis. Units: platelets/liter | every 6 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days |
| Change in red cell distribution width | Red cell distribution width is a measure of the range of variation of red blood cell volume. Units: no units | every 6 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days |
| Change in blood albumin level | Liver function test Units: gram/deciliter | every 6 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days |
| Change in serum alkaline phosphatase level | Liver function test Units: international units/liter | every 6 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days |
| Change in serum aspartate transaminase level | Liver function test Units: international units/liter | every 6 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days |
| Change in serum alanine aminotransferase level | Liver function test Units: international units/liters | every 6 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days |
| Change in blood urea nitrogen levels | Kidney function test Units: milligram/deciliter | every 6 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days |
| Change in serum calcium level | Kidney function test Units: milligram/deciliter | every 6 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days |
| Change in serum chloride level | Kidney function test Units: millimole/liter | every 6 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days |
| Change in serum potassium level | Kidney function test Units: millimole/liter | every 6 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days |
| Change in serum creatinine level | Kidney function test Units: gram/deciliter | every 6 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days |
| Date patient is re-intubated or need mechanical ventilation for a second time | If the patient needs mechanical ventilation for a second time, this information will be collected. | Up to 10 days |
| Length of intensive care unit stay | Time from intensive care unit admission until death or transfer to hospital bed. | Up to 10 days |
| The total hospital stay | Time from hospital admission to discharge from the hospital. This information will be collected. | Up to 10 days |
| Disposition at discharge | Once the patient feels better and can leave the hospital, he/she will be discharged. The place of discharge (e.g. home, rehab facility, nursing home, etc), time and date will be collected. | Up to 10 days |
| Change in heart rate | Heart rate: is the number of times a person's heart beats per minute | every 6 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days |
| Change in the dosage of vasopressor medication | Units: milligram | every 6 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days |
Units: milligram/deciliter
| At baseline and every 24 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days |
| Change in blood high-density lipoprotein level | Units: milligram/deciliter | At baseline and every 24 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days |
| Change in blood triglycerides level | Units: milligram/deciliter | At baseline and every 24 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days |
| Change in blood glucose level | Glucose: sugar in blood. Units: millimole/liter | At baseline and every 24 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days |
| Change in blood glucagon level | Glucagon: hormone release by pancreas that increase concentration of glucose in blood. Units: nanogram/liter | At baseline and every 24 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days |
| Change in blood free fatty acids level | Free fatty acids are fatty acids that are produced from triglycerides and are measure in blood. | At baseline and every 24 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days |
| Change in blood insulin levels | Hormone that regulates glucose. Units: insulin units/liter | At baseline and every 24 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days |
| Change in blood leptin levels | Leptin helps regulate and alter long-term food intake and energy expenditure. Units: nanogram/deciliter | At baseline and every 24 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days |
| Change in blood insulin like growth factor 1 levels | Units: nanomole/liter | At baseline and every 24 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days |
| Change in blood C-reactive protein levels | C-reactive protein is a protein made by the liver that measures inflammation (e.g. pancreatitis). Units: microgram/milliliter | At baseline and every 24 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days |
| Change in blood interleukin-1β levels | Cytokines are signaling molecules that measure inflammation. | At baseline and every 24 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days |
| Change in blood interleukin-6 levels | Cytokines are signaling molecules that measure inflammation. | At baseline and every 24 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days |
| Change in blood interleukin-18 levels | Cytokines are signaling molecules that measure inflammation. | At baseline and every 24 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days |
| Change in blood tumor necrosis factor alpha levels | Cytokines are signaling molecules that measure inflammation. | At baseline and every 24 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days |
| Change in blood C-C motif chemokine ligand 2 (CCL2) levels | Chemokine that mediates inflammation. | At baseline and every 24 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days |
| Change in blood C-C motif chemokine ligand 3 (CCL3) levels | Chemokine that mediates inflammation. | At baseline and every 24 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days |
| Change in blood C-C motif chemokine ligand 4 (CCL4) levels | Chemokine that mediates inflammation. | At baseline and every 24 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days |
| Change in blood B cell-attracting chemokine 1 (CXCL13) levels | Chemokine that mediates inflammation. | At baseline and every 24 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days |
| Change in blood ferritin levels | Ferritin stores iron inside of cells. Units: nanogram/milliliter | At baseline and every 24 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days |
| Change in blood betahydroxybutyrate levels | Units: millimole/liter | At baseline and every 24 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days |
| Change in blood urine acetoacetate levels | Units: millimole/liter | At baseline and every 24 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days |
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| 15328567 | Background | Baumeister FA, Oberhoffer R, Liebhaber GM, Kunkel J, Eberhardt J, Holthausen H, Peters J. Fatal propofol infusion syndrome in association with ketogenic diet. Neuropediatrics. 2004 Aug;35(4):250-2. doi: 10.1055/s-2004-820992. |
| 30803732 | Background | Brozova K, Broz J. The risk of hypoglycemia and the ketogenic diet for super-refractory status epilepticus patients. Brain Dev. 2019 Sep;41(8):740. doi: 10.1016/j.braindev.2019.02.008. Epub 2019 Feb 22. No abstract available. |
| 27060389 | Background | Cervenka MC, Henry BJ, Felton EA, Patton K, Kossoff EH. Establishing an Adult Epilepsy Diet Center: Experience, efficacy and challenges. Epilepsy Behav. 2016 May;58:61-8. doi: 10.1016/j.yebeh.2016.02.038. Epub 2016 Apr 6. |
| 28110175 | Background | van der Louw EJ, Williams TJ, Henry-Barron BJ, Olieman JF, Duvekot JJ, Vermeulen MJ, Bannink N, Williams M, Neuteboom RF, Kossoff EH, Catsman-Berrevoets CE, Cervenka MC. Ketogenic diet therapy for epilepsy during pregnancy: A case series. Seizure. 2017 Feb;45:198-201. doi: 10.1016/j.seizure.2016.12.019. Epub 2016 Dec 26. |
| 29881797 | Background | Kossoff EH, Zupec-Kania BA, Auvin S, Ballaban-Gil KR, Christina Bergqvist AG, Blackford R, Buchhalter JR, Caraballo RH, Cross JH, Dahlin MG, Donner EJ, Guzel O, Jehle RS, Klepper J, Kang HC, Lambrechts DA, Liu YMC, Nathan JK, Nordli DR Jr, Pfeifer HH, Rho JM, Scheffer IE, Sharma S, Stafstrom CE, Thiele EA, Turner Z, Vaccarezza MM, van der Louw EJTM, Veggiotti P, Wheless JW, Wirrell EC; Charlie Foundation; Matthew's Friends; Practice Committee of the Child Neurology Society. Optimal clinical management of children receiving dietary therapies for epilepsy: Updated recommendations of the International Ketogenic Diet Study Group. Epilepsia Open. 2018 May 21;3(2):175-192. doi: 10.1002/epi4.12225. eCollection 2018 Jun. |
| 32119827 | Background | Correction to Lancet Respir Med 2020; published online Feb 21. https://doi.org/10.1016/S2213-2600(20)30079-5. Lancet Respir Med. 2020 Apr;8(4):e26. doi: 10.1016/S2213-2600(20)30103-X. Epub 2020 Feb 28. No abstract available. |
| D014777 |
| Virus Diseases |
| D003333 | Coronaviridae Infections |
| D030341 | Nidovirales Infections |
| D012327 | RNA Virus Infections |
| D008171 | Lung Diseases |
| D012140 | Respiratory Tract Diseases |
| D004032 |
| Diet |
| D009747 | Nutritional Physiological Phenomena |
| D000066888 | Diet, Food, and Nutrition |
| D010829 | Physiological Phenomena |
| D019984 | Quality Indicators, Health Care |
| D011787 | Quality of Health Care |
| D006298 | Health Services Administration |
| D017530 | Health Care Quality, Access, and Evaluation |