Ketogenic Diet and CPAP Previous Bariatric Surgery
Ketogenic Diet and CPAP Previous Bariatric Surgery
Obstructive Sleep Apnea Syndrome (OSAS) and obesity tend to coexist and are often associated
 with arterial hypertension, dyslipidaemia, and insulin resistance [1]. Polysomnography (PSG)
 is the standard technique for diagnosing OSAS and determining its severity [2]. The results
 of the examination provide the Apnea-Hypopnea Index [AHI], or the Respiratory Disturbance
 Index [RDI]), which will be used to quantify apnea and classify its severity based on an
 international score. In general, an AHI scoring less than 5 is considered "normal" (5-15 mild
 sleep apnea; >15 moderate sleep apnea; ≥30 severe sleep apnea).

 In order to improve those parameters in obese patients who have been diagnosed with OSAS and
 are candidates for BS (BS), national and international guidelines recommend preoperative CPAP
 (Continuous Positive Airway Pressure) treatment in order to reduce anaesthesia risks [3-6].
 Furthermore, several studies report that obese OSAS patients benefit from preoperative weight
 loss [1,7] (in terms of AHI index, night snoring and arterial hypertension).

 Obese patients who are candidates for BS often go on a preoperative diet in order to decrease
 weight and liver volume (especially of the left lobe) and correct any vitamin/mineral
 deficiency. The results of a recently published study show that 4 weeks of Ketogenic
 Micronutrient Enriched Diet (KMED) significantly reduce body weight, liver lobe volume and
 vitamin/mineral deficiencies in obese patients who prepare to undergo BS [8], with resulting
 foreseeable reduction of intraoperative complications and surgical time.

 To date, there are no prospective multicenter randomized trials demonstrating whether a
 preoperative ketogenic diet associated with CPAP use improves OSAS versus treatment with CPAP
 alone, with the possibility of reducing the preoperative treatment period.

 Aim of the study: To assess the clinical advantage in combining two preoperative strategies
 (CPAP + KMED) compared to preoperative treatment with CPAP alone, for the reduction of
 surgical risks in morbidly obese patients with severe OSAS who are scheduled for BS.
A recent clinical study published in 2014 on the New England Journal of Medicine found that
 often even an initial modest body weight reduction can favourably modify apnea events and
 severity during the night, with the latter that can be reduced by about 30% (AHI) for a 10%
 weight reduction compared to the initial weight [1]. However, considering the average AHI
 data reported by the authors, which do not include post-treatment information, statistical
 elements at our disposal are insufficient to assess the "effect size". Therefore, a sample of
 65 patients per group will be needed for the evaluation of the primary endpoint (statistical
 significance of 5% [two-tailed], 80% power, "effect size" 0.25, calculated using the G* Power
 software, Düsseldorf, Germany). A total of 144 patients will be enrolled (24 patients per
 participating site) on the baseline assumption of a dropout of 10%. Most drop-outs may result
 from CPAP use and, in particular, discomfort experienced by the patient with tube and facial
 mask, difficult acceptance because of psychological reasons (shame or negative expectations
 in terms of partner judgment), or subjective feeling of claustrophobic suffocation or
 anxiety. The expected drop-out for KMED with the Ketocompleat protocol is 15%. Indeed, in
 Schiavo et al [8] study, most patients (86%) showed high acceptability of the Ketocompleat
 ketogenic protocol prescribed in the four weeks of preoperative treatment, and the only side
 effect reported was mild headache with associated modest halitosis, especially during the
 initial treatment days, which, however, did not prevent patients from continuing with the
 protocol.

 Experiment design and patient randomization

 Spontaneous, prospective, comparative and multicentre trial including 144 patients with
 severe OSAS (polysomnogram with AHI≥30) suitable for gastric bypass surgery, and randomized
 into 2 groups:

 GROUP 1: 72 morbidly obese patients (12 patients per participating site) with severe OSAS and
 suitable for gastric bypass surgery, who underwent 4 weeks of CPAC treatment (these patients
 will not be required to change their eating habits) according to the standard; GROUP 2: 72
 morbidly obese patients (12 patients per participating site) with severe OSAS and BS
 candidates who underwent CPAC + KMED treatment for 4 weeks.

 Randomization will be conducted via permuted-block design (PBD), with stratification of
 patients based on age, gender, and enrollement site (24 patients per participating site, 12
 per study group) Preoperative ketogenic micronutrient-enriched diet: The ketogenic diet has
 been used for many years in clinical settings [9]. Given its safety and effectiveness in
 determining weight loss, associated with optimal adherence and patient compliance, the
 ketogenic diet has recently been used by several obesity surgery centers in the preoperative
 management of obese patients who are candidates for BS [8, 10-11]. The validated Ketocompleat
 protocol [8] will serve as the KMED of choice. In particular, the protocol will provide a
 diet with ketogenic characteristics that patients will have to follow for breakfast, snack,
 lunch and snack, and replacement of the evening meal with the Ketocompleat ketogenic
 supplement. Figure 1 shows a daily diet sample.

 In short, to ensure that all patients follow the same diet, the investigator will use the
 software (https://www.eatthismuch.com) to develop two ketogenic diet plans (plan 1, days
 1-14; plan 2, days 15-28), containing specific amounts of foods to be consumed. Each
 ketogenic plan will comprise: 1150 to 1250 kcal/day, of which 4% carbohydrates, 71% fat, and
 25% proteins. The composition of the supplement to use for the trial (Ketocompleat, MVMedical
 Solutions, Serravalle, Republic of San Marino) is shown in Table 1. Ketocompleat is a
 supplement included in the Ministry of Health's food supplement register (code 94721); given
 its carbohydrate-free formulation, it can easily be associated to a low-carbohydrate
 ketogenic diet. The diet plans and the Ketocompleat supplement will be provided free of
 charge to all trial participants by MVMedical Solutions, which will have no role in designing
 trial and patient enrollement in the different participating sites, or in processing any
 trial-related data.

 Patient adherence to the prescribed preoperative diet will be confirmed through the following
 scientifically validated tests: 3-Day Estimated Food and Records and 72-h Recalls [8], while
 the presence of ketone bodies in the urine (Ketur-Test, Roche Diagnostic, Milan, Italy)
 associated with weight loss will be used as the patient compliance index. The Ketur test will
 be performed in outpatient mode during the weekly diet check.

 Polysomnography

 Polysomnography is a sleep study that collects a variety of parameters and conditions, such
 as oxygen saturation, heart rate, presence (or absence in the case of apnea) of airflow
 through mouth and nose, presence (or absence) of thoracic and abdominal movements, position
 held by the subject during sleep, and snoring during sleep. By analysing these data, it will
 be possible to define: number of episodes of haemoglobin desaturation during sleep
 (desaturation index per hour - ODIindex), presence or absence of apnea during sleep,
 differentiating between true apnea true (absence of air flow) and hypopneas (air flow
 present, though substantially reduced), determination of "obstructive" "central" or "mixed"
 apnea/hypopnea, hourly frequency of apnea/ hypopnea ( apnea/hypopnea events per hour or AHI
 index), which allows defining the degree of severity of the disorder (disease stage), AHI in
 supine and non-supine position (often this datum documents greater apnea frequency in the
 supine position compared to data relating to the patient in lateral decubitus), and snoring
 time during sleep. In order to evaluate the clinical advantage offered by the combination of
 the two preoperative strategies (CPAP and ketogenic diet therapy) compared to CPAP
 preoperative treatment alone, for the reduction of the surgical risk in morbidly obese OSAS
 BS candidates, patients of both groups will undergo polysomnography before the trial and
 after 4 weeks of CPAP alone or combined CPAP + KMED treatment. The tolerance interval for PSG
 execution at the end of the treatment is 7 days; otherwise, patients will be considered
 drop-outs.

 CPAP-type ventilator prescription CPAP use is the gold standard for the treatment of sleep
 apnea syndrome. The CPAP device consists of a small fan connected to the patient through a
 tube and a facial mask (nasal or oronasal). This device provides continuous air flow that
 maintains the airways open, preventing the collapse (closing) of the critical points
 responsible for respiratory obstruction during sleep, thus avoiding or limiting sleep apnea.
 Patients with severe OSAS who are BS candidates will be treated with CPAP only at night
 (Group 1), or CPAP at night + KMED daily (Group 2), for 4 weeks.

 Preoperative investigations and after 4 weeks of CPAP or CPAP + KMED treatment

 In the BS Centers participating in the trial, both experimental groups will undergo the
 following evaluation:

 -  Complete blood count with WBC differential, triglycerides, total cholesterol, HDL
 cholesterol, LDL cholesterol, triglycerides, GOT, GPT, ΥGT, nitrogen, creatinine, urea,
 iron, ferritin, ketone bodies, baseline glucose, baseline insulin, and CRP

 -  Body weight, height and BMI calculation

 -  Waist and hip circumference

 -  Chest X-ray

 -  Blood gas analysis

 -  Spirometry

 -  Polysomnography

 Laboratory/instrumental clinical analyses, polysomnography and CPAP will be performed in the
 sites participating in the project; data obtained will be evaluated by a Pneumologist, while
 the statistical analysis will be entrusted to a Biostatistician.

 Inclusion criteria: patients of both sexes with BMI ≥35 with severe OSAS; age between 18-65
 years; non-smokers or who have quit smoking for at least 3 months.

 Exclusion criteria: kidney and/or liver conditions that would make a KMED diet unsuitable
 (creatinine levels >1.8 mg/dL or liver enzyme levels (glutamic pyruvic transaminase [GPT] or
 glutamic oxaloacetic transaminase [GOT]) less than three times over the upper normal
 threshold, and psychological problems that would make CPAP treatment problematic. Patients
 with obesity >60 BMI.

 Primary endpoint: evaluate the effect of combined (CPAP + KMED) therapy vs CPAP on the AHI
 after 4 weeks. Secondary end points: evaluate CRP levels, arterial pressure and lipid panel
 (total cholesterol, HDL, LDL and triglycerides) in the two study groups.
Inclusion Criteria:

 -  BMI ≥35 Kg/m2

 -  Severe OSAS

 -  Non-smokers or who have quit smoking for at least 3 months

 Exclusion Criteria:

 -  kidney and/or liver conditions that would make a KMED diet unsuitable (creatinine
 levels >1.8 mg/dL or liver enzyme levels (glutamic pyruvic transaminase [GPT] or
 glutamic oxaloacetic transaminase [GOT]) less than three times over the upper normal
 threshold

 -  psychological problems that would make CPAP treatment problematic

 -  BMI > 60 Kg/m2