Keto-diet for Intubated Critical Care COVID-19

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.