Clinical trial NCT04358835: Keto-diet for Intubated Critical Care COVID-19
Official title: Keto-diet for Intubated Critical Care COVID-19 (KICC-COVID19)
Study type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: NA
Conditions: COVID-19
Keywords: ketogenic diet
Intensive care
COVID-19
Mechanical ventilation
Intubated patients
coronavirus
Lead sponsor: Johns Hopkins University
Sponsor class: OTHER
First posted: 2020-04-24
Enrollment: 0
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention 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.
Primary purpose: TREATMENT

Brief 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. 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.

Eligibility criteria: 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

Primary outcomes:
measure: Change in the partial pressure of carbon dioxide (PaCO2)
timeFrame: Daily until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days
Secondary outcomes:
measure: Change in minute ventilation
timeFrame: every 6 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days
measure: Change in respiratory system compliance
timeFrame: every 6 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days
measure: Change in driving pressure
timeFrame: every 6 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days
measure: Change in ventilator synchrony
timeFrame: every 6 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days
measure: Change in mean arterial pressure
timeFrame: every 6 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days
measure: Change in the fraction of inspired oxygen percentage of oxygen (FiO2)
timeFrame: every 6 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days
measure: Change in the partial pressure of carbon dioxide (PaO2) to the fraction of inspired oxygen percentage of oxygen (FiO2) ratio
timeFrame: every 6 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days
measure: Change in hydrogen ion activity (pH)
timeFrame: every 6 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days
measure: Change in Bicarbonate (HCO3)
timeFrame: every 6 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days
measure: Change in red blood cell count
timeFrame: every 6 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days
measure: Change in white blood cell count
timeFrame: every 6 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days
measure: Change in white cell differential
timeFrame: every 6 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days
measure: Change in hemoglobin levels
timeFrame: every 6 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days
measure: Change in hematocrit
timeFrame: every 6 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days
measure: Change in mean cell volume
timeFrame: every 6 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days
measure: Change in mean cell hemoglobin
timeFrame: every 6 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days
measure: Change in mean cell hemoglobin concentration
timeFrame: every 6 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days
measure: Change in platelet count
timeFrame: every 6 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days
measure: Change in red cell distribution width
timeFrame: every 6 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days
measure: Change in blood albumin level
timeFrame: every 6 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days
measure: Change in serum alkaline phosphatase level
timeFrame: every 6 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days
measure: Change in serum aspartate transaminase level
timeFrame: every 6 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days
measure: Change in serum alanine aminotransferase level
timeFrame: every 6 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days
measure: Change in blood urea nitrogen levels
timeFrame: every 6 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days
measure: Change in serum calcium level
timeFrame: every 6 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days
measure: Change in serum chloride level
timeFrame: every 6 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days
measure: Change in serum potassium level
timeFrame: every 6 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days
measure: Change in serum creatinine level
timeFrame: every 6 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days
measure: Date patient is re-intubated or need mechanical ventilation for a second time
timeFrame: Up to 10 days
measure: Length of intensive care unit stay
timeFrame: Up to 10 days
measure: The total hospital stay
timeFrame: Up to 10 days
measure: Disposition at discharge
timeFrame: Up to 10 days
measure: Change in heart rate
timeFrame: every 6 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days
measure: Change in the dosage of vasopressor medication
timeFrame: every 6 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days
Other outcomes:
measure: Change in total blood cholesterol level
timeFrame: At baseline and every 24 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days
measure: Change in blood low-density lipoprotein level
timeFrame: At baseline and every 24 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days
measure: Change in blood high-density lipoprotein level
timeFrame: At baseline and every 24 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days
measure: Change in blood triglycerides level
timeFrame: At baseline and every 24 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days
measure: Change in blood glucose level
timeFrame: At baseline and every 24 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days
measure: Change in blood glucagon level
timeFrame: At baseline and every 24 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days
measure: Change in blood free fatty acids level
timeFrame: At baseline and every 24 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days
measure: Change in blood insulin levels
timeFrame: At baseline and every 24 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days
measure: Change in blood leptin levels
timeFrame: At baseline and every 24 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days
measure: Change in blood insulin like growth factor 1 levels
timeFrame: At baseline and every 24 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days
measure: Change in blood C-reactive protein levels
timeFrame: At baseline and every 24 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days
measure: Change in blood interleukin-1β levels
timeFrame: At baseline and every 24 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days
measure: Change in blood interleukin-6 levels
timeFrame: At baseline and every 24 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days
measure: Change in blood interleukin-18 levels
timeFrame: At baseline and every 24 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days
measure: Change in blood tumor necrosis factor alpha levels
timeFrame: At baseline and every 24 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days
measure: Change in blood C-C motif chemokine ligand 2 (CCL2) levels
timeFrame: At baseline and every 24 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days
measure: Change in blood C-C motif chemokine ligand 3 (CCL3) levels
timeFrame: At baseline and every 24 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days
measure: Change in blood C-C motif chemokine ligand 4 (CCL4) levels
timeFrame: At baseline and every 24 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days
measure: Change in blood B cell-attracting chemokine 1 (CXCL13) levels
timeFrame: At baseline and every 24 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days
measure: Change in blood ferritin levels
timeFrame: At baseline and every 24 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days
measure: Change in blood betahydroxybutyrate levels
timeFrame: At baseline and every 24 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days
measure: Change in blood urine acetoacetate levels
timeFrame: At baseline and every 24 hours until the patient is wean off the ventilator or die, whichever came first, assessed up to 10 days
Locations:
Study officials:
affiliation: Johns Hopkins University
name: Mackenzie Cervenka, MD
role: PRINCIPAL_INVESTIGATOR
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