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.

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.

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.

Daily until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days

every 6 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days

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

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

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

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

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

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

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

every 6 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days

every 6 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days

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

every 6 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days

every 6 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days

every 6 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days

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

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

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

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

every 6 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days

every 6 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days

every 6 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days

every 6 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days

every 6 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days

every 6 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days

every 6 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days

every 6 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days

every 6 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days

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.

every 6 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days

every 6 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days

At baseline and every 24 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days

At baseline and every 24 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days

At baseline and every 24 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days

At baseline and every 24 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days

At baseline and every 24 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days

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

At baseline and every 24 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days

At baseline and every 24 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days

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

At baseline and every 24 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days

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

At baseline and every 24 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days

At baseline and every 24 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days

At baseline and every 24 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days

At baseline and every 24 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days

At baseline and every 24 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days

At baseline and every 24 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days

At baseline and every 24 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days

At baseline and every 24 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days

At baseline and every 24 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days

At baseline and every 24 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days

At baseline and every 24 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days

Inclusion Criteria: Patients age 18 and older. COVID-19 positive and respiratory failure requiring intubation Legally authorized representative Exclusion Criteria: 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

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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.

Severe Outcomes Among Patients with Coronavirus Disease 2019 (COVID-19) - United States, February 12-March 16, 2020