COVID-19KICC-COVID19NCT04358835
Keto-diet for Intubated Critical Care COVID-19
A study testing Ketogenic diet in people with COVID-19, run by Johns Hopkins University.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 18 to 80 years
- Conditions the study is for
- COVID-19
- What is being tested?
- Ketogenic diet
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 0 participants
- Where
- No sites listed yet
- Study dates
- 1 Sep 2020to 31 Dec 2021
- Phase
- Interventional
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 80 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Patients age 18 and older.
- COVID-19 positive and respiratory failure requiring intubation
- Legally authorized representative
Who cannot join
- Unstable metabolic condition
- Liver failure
- Acute Pancreatitis
- Inability to tolerate enteral feeds, ileus, gastrointestinal bleeding
- Known Pregnancy
- Received propofol infusion within 24 hours
- Known fatty acid oxidation disorder or pyruvate carboxylase deficiency
About this study
Official title: Keto-diet for Intubated Critical Care COVID-19 (KICC-COVID19)
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.
Read the detailed description
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.
- Conditions
- COVID-19
- Being tested
- Ketogenic diet, standard of care
- Keywords
- ketogenic diet, Intensive care, COVID-19, Mechanical ventilation, Intubated patients, coronavirus
- Medical subject headings
- COVID-19, Coronavirus Infections
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Ketogenic dietDietary supplement
4:1 ratio enteral ketogenic formula within 48 hours of intubation
standard of careOther
standard of care/supportive therapy
| Study group | Role | What they receive |
|---|---|---|
| Intubated patients with COVID-19 on a ketogenic diet only | Experimental | 4:1 ketogenic diet formula Receives: Dietary Supplement: Ketogenic diet; Other: standard of care |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change in the partial pressure of carbon dioxide (PaCO2)
PaCO2 is the partial pressure of carbon dioxide Units: millimeters of mercury
Measured: Daily until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days
Secondary outcomes (34)
Change in minute ventilation
Minute ventilation is the product of respiratory rate and tidal volume. Units: Liter per minute
Measured: 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
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
Measured: 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
Measured: 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
Measured: 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
Measured: 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: %
Measured: 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
Measured: 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.
Measured: 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
Measured: 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
Measured: 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
Measured: 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: %
Measured: 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
Measured: 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: %
Measured: 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
Measured: 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
Measured: 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: %
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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.
Measured: Up to 10 days
Length of intensive care unit stay
Time from intensive care unit admission until death or transfer to hospital bed.
Measured: Up to 10 days
The total hospital stay
Time from hospital admission to discharge from the hospital. This information will be collected.
Measured: 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.
Measured: Up to 10 days
Change in heart rate
Heart rate: is the number of times a person's heart beats per minute
Measured: 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
Measured: every 6 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted24 Apr 2020
- Study start1 Sep 2020 (estimated)
- Primary completion1 Sep 2021 (estimated)
- Study completion31 Dec 2021 (estimated)
Why it stopped: Study did not begin enrollment, multiple competing studies at same institution
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (33)Papers the sponsor has linked to this study.
- Other trials for COVID-19Studies of the same condition, open and under way.
- More trials run by Johns Hopkins UniversityThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Model description
- 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.
- Masking
- None (open label)
- Enrolment
- 0 participants (actual)
Sponsor and investigators
- Lead sponsor
- Johns Hopkins University
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Mackenzie Cervenka, MD, Principal investigator, Johns Hopkins University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04358835
- Sponsor's protocol ID
- IRB00247383
- Acronym
- KICC-COVID19
- Status last verified
- Aug 2020
- First submitted
- 16 Apr 2020
- Last updated
- 25 Aug 2020
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
Publications
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.
PubMed 32109372al-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.
PubMed 2504796van den Berg B, Bogaard JM, Hop WC. High fat, low carbohydrate, enteral feeding in patients weaning from the ventilator. Intensive Care Med. 1994 Aug;20(7):470-5. doi: 10.1007/BF01711897.
PubMed 7995861Cervenka MC, Hartman AL, Venkatesan A, Geocadin RG, Kossoff EH. The ketogenic diet for medically and surgically refractory status epilepticus in the neurocritical care unit. Neurocrit Care. 2011 Dec;15(3):519-24. doi: 10.1007/s12028-011-9546-3.
PubMed 21523523Cervenka MC, Hocker S, Koenig M, Bar B, Henry-Barron B, Kossoff EH, Hartman AL, Probasco JC, Benavides DR, Venkatesan A, Hagen EC, Dittrich D, Stern T, Radzik B, Depew M, Caserta FM, Nyquist P, Kaplan PW, Geocadin RG. Phase I/II multicenter ketogenic diet study for adult superrefractory status epilepticus. Neurology. 2017 Mar 7;88(10):938-943. doi: 10.1212/WNL.0000000000003690. Epub 2017 Feb 8.
PubMed 28179470McDonald TJW, Cervenka MC. Ketogenic Diets for Adults With Highly Refractory Epilepsy. Epilepsy Curr. 2017 Nov-Dec;17(6):346-350. doi: 10.5698/1535-7597.17.6.346.
PubMed 29217974Williams TJ, Cervenka MC. The role for ketogenic diets in epilepsy and status epilepticus in adults. Clin Neurophysiol Pract. 2017 Jul 1;2:154-160. doi: 10.1016/j.cnp.2017.06.001. eCollection 2017.
PubMed 30214989Thakur KT, Probasco JC, Hocker SE, Roehl K, Henry B, Kossoff EH, Kaplan PW, Geocadin RG, Hartman AL, Venkatesan A, Cervenka MC. Ketogenic diet for adults in super-refractory status epilepticus. Neurology. 2014 Feb 25;82(8):665-70. doi: 10.1212/WNL.0000000000000151. Epub 2014 Jan 22.
PubMed 24453083McDonald TJW, Henry-Barron BJ, Felton EA, Gutierrez EG, Barnett J, Fisher R, Lwin M, Jan A, Vizthum D, Kossoff EH, Cervenka MC. Improving compliance in adults with epilepsy on a modified Atkins diet: A randomized trial. Seizure. 2018 Aug;60:132-138. doi: 10.1016/j.seizure.2018.06.019. Epub 2018 Jun 22.
PubMed 29960852Park EG, Lee J, Lee J. The ketogenic diet for super-refractory status epilepticus patients in intensive care units. Brain Dev. 2019 May;41(5):420-427. doi: 10.1016/j.braindev.2018.12.007. Epub 2019 Jan 9.
PubMed 30638692Peng P, Peng J, Yin F, Deng X, Chen C, He F, Wang X, Guang S, Mao L. Ketogenic Diet as a Treatment for Super-Refractory Status Epilepticus in Febrile Infection-Related Epilepsy Syndrome. Front Neurol. 2019 Apr 26;10:423. doi: 10.3389/fneur.2019.00423. eCollection 2019.
PubMed 31105638Fried PI, McClean PA, Phillipson EA, Zamel N, Murray FT, Marliss EB. Effect of ketosis on respiratory sensitivity to carbon dioxide in obesity. N Engl J Med. 1976 May 13;294(20):1081-6. doi: 10.1056/NEJM197605132942003.
PubMed 1256524Tagliabue A, Bertoli S, Trentani C, Borrelli P, Veggiotti P. Effects of the ketogenic diet on nutritional status, resting energy expenditure, and substrate oxidation in patients with medically refractory epilepsy: a 6-month prospective observational study. Clin Nutr. 2012 Apr;31(2):246-9. doi: 10.1016/j.clnu.2011.09.012. Epub 2011 Oct 20.
PubMed 22019282Rubini A, Bosco G, Lodi A, Cenci L, Parmagnani A, Grimaldi K, Zhongjin Y, Paoli A. Effects of Twenty Days of the Ketogenic Diet on Metabolic and Respiratory Parameters in Healthy Subjects. Lung. 2015 Dec;193(6):939-45. doi: 10.1007/s00408-015-9806-7. Epub 2015 Sep 26.
PubMed 26410589Ruskin DN, Ross JL, Kawamura M Jr, Ruiz TL, Geiger JD, Masino SA. A ketogenic diet delays weight loss and does not impair working memory or motor function in the R6/2 1J mouse model of Huntington's disease. Physiol Behav. 2011 Jul 6;103(5):501-7. doi: 10.1016/j.physbeh.2011.04.001. Epub 2011 Apr 9.
PubMed 21501628
Study at a glance
From the registry record, last updated by the sponsor on 25 Aug 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Keto-diet for Intubated Critical Care COVID-19 (KICC-COVID19)
- ClinicalTrials.gov ID
- NCT04358835
- Acronym / sponsor ID
- KICC-COVID19 / IRB00247383
- Conditions
- COVID-19
- Keywords
- ketogenic diet, Intensive care, COVID-19, Mechanical ventilation, Intubated patients, coronavirus
- Study type
- Interventional
- Recruitment status
- WithdrawnReason stopped: Study did not begin enrollment, multiple competing studies at same institution
- Enrolment
- 0 participants (actual)
- Lead sponsor
- Johns Hopkins UniversityUniversity, hospital or other
- Study start
- 1 Sep 2020 (estimated)
- Primary completion
- 1 Sep 2021 (estimated)
- Study completion
- 31 Dec 2021 (estimated)
- First posted
- 24 Apr 2020 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
- Model description
- 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.
| Arm | Type | Receives |
|---|---|---|
| Intubated patients with COVID-19 on a ketogenic diet only | Experimental | Dietary Supplement: Ketogenic diet, Other: standard of care4:1 ketogenic diet formula |
Who may qualify
- Ages
- 18 to 80 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (3 listed)
- Patients age 18 and older.
- COVID-19 positive and respiratory failure requiring intubation
- Legally authorized representative
Key exclusion criteria (7 listed)
- Unstable metabolic condition
- Liver failure
- Acute Pancreatitis
- Inability to tolerate enteral feeds, ileus, gastrointestinal bleeding
- Known Pregnancy
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Ketogenic diet4:1 ratio enteral ketogenic formula within 48 hours of intubation | Dietary supplement | Intubated patients with COVID-19 on a ketogenic diet only |
| standard of carestandard of care/supportive therapy | Other | Intubated patients with COVID-19 on a ketogenic diet only |
Primary outcome
Change in the partial pressure of carbon dioxide (PaCO2)
Time frame: Daily until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days
PaCO2 is the partial pressure of carbon dioxide Units: millimeters of mercury
34 secondary outcomes
Change in minute ventilation
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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)
Time frame: 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
Time frame: 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)
Time frame: 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)
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: every 6 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days
Change in hematocrit
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: Up to 10 days
Length of intensive care unit stay
Time frame: Up to 10 days
The total hospital stay
Time frame: Up to 10 days
Disposition at discharge
Time frame: Up to 10 days
Change in heart rate
Time frame: 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
Time frame: every 6 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days
Results and safety
The study was withdrawn before enrolling participants, so there are no results.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 25 Aug 2020.
- Background: PubMed 32109372Ji 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.
- Background: PubMed 2504796al-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.
- Background: PubMed 7995861van den Berg B, Bogaard JM, Hop WC. High fat, low carbohydrate, enteral feeding in patients weaning from the ventilator. Intensive Care Med. 1994 Aug;20(7):470-5. doi: 10.1007/BF01711897.
- Background: PubMed 21523523Cervenka MC, Hartman AL, Venkatesan A, Geocadin RG, Kossoff EH. The ketogenic diet for medically and surgically refractory status epilepticus in the neurocritical care unit. Neurocrit Care. 2011 Dec;15(3):519-24. doi: 10.1007/s12028-011-9546-3.
- Background: PubMed 28179470Cervenka MC, Hocker S, Koenig M, Bar B, Henry-Barron B, Kossoff EH, Hartman AL, Probasco JC, Benavides DR, Venkatesan A, Hagen EC, Dittrich D, Stern T, Radzik B, Depew M, Caserta FM, Nyquist P, Kaplan PW, Geocadin RG. Phase I/II multicenter ketogenic diet study for adult superrefractory status epilepticus. Neurology. 2017 Mar 7;88(10):938-943. doi: 10.1212/WNL.0000000000003690. Epub 2017 Feb 8.
- Background: PubMed 29217974McDonald TJW, Cervenka MC. Ketogenic Diets for Adults With Highly Refractory Epilepsy. Epilepsy Curr. 2017 Nov-Dec;17(6):346-350. doi: 10.5698/1535-7597.17.6.346.
- Background: PubMed 30214989Williams TJ, Cervenka MC. The role for ketogenic diets in epilepsy and status epilepticus in adults. Clin Neurophysiol Pract. 2017 Jul 1;2:154-160. doi: 10.1016/j.cnp.2017.06.001. eCollection 2017.
- Background: PubMed 24453083Thakur KT, Probasco JC, Hocker SE, Roehl K, Henry B, Kossoff EH, Kaplan PW, Geocadin RG, Hartman AL, Venkatesan A, Cervenka MC. Ketogenic diet for adults in super-refractory status epilepticus. Neurology. 2014 Feb 25;82(8):665-70. doi: 10.1212/WNL.0000000000000151. Epub 2014 Jan 22.
- Background: PubMed 29960852McDonald TJW, Henry-Barron BJ, Felton EA, Gutierrez EG, Barnett J, Fisher R, Lwin M, Jan A, Vizthum D, Kossoff EH, Cervenka MC. Improving compliance in adults with epilepsy on a modified Atkins diet: A randomized trial. Seizure. 2018 Aug;60:132-138. doi: 10.1016/j.seizure.2018.06.019. Epub 2018 Jun 22.
- Background: PubMed 30638692Park EG, Lee J, Lee J. The ketogenic diet for super-refractory status epilepticus patients in intensive care units. Brain Dev. 2019 May;41(5):420-427. doi: 10.1016/j.braindev.2018.12.007. Epub 2019 Jan 9.
- Background: PubMed 31105638Peng P, Peng J, Yin F, Deng X, Chen C, He F, Wang X, Guang S, Mao L. Ketogenic Diet as a Treatment for Super-Refractory Status Epilepticus in Febrile Infection-Related Epilepsy Syndrome. Front Neurol. 2019 Apr 26;10:423. doi: 10.3389/fneur.2019.00423. eCollection 2019.
- Background: PubMed 1256524Fried PI, McClean PA, Phillipson EA, Zamel N, Murray FT, Marliss EB. Effect of ketosis on respiratory sensitivity to carbon dioxide in obesity. N Engl J Med. 1976 May 13;294(20):1081-6. doi: 10.1056/NEJM197605132942003.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Mackenzie Cervenka, MD principal investigator
Johns Hopkins University
Questions about this trial
What is this clinical trial studying?
A study testing Ketogenic diet in people with COVID-19, run by Johns Hopkins University.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 7 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: withdrawn, as of the sponsor's last update on 25 Aug 2020. Status can change between updates, so confirm with the study contact before making plans.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study was withdrawn before enrolling participants, so there are no results.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in the partial pressure of carbon dioxide (PaCO2) (time frame: Daily until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04358835, which also lists 33 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 25 Aug 2020.