High Flow Nasal Cannula in Severe Sepsis
High Flow Nasal Cannula in Severe Sepsis
Severe sepsis leads a high morbidity and mortality by causing organ damage at distance. The
 treatment relies on early antibiotic therapy and hemodynamic resuscitation. Hypothesis: high
 flow nasal cannula (HFNC) could reduce work of breathing and improve the outcome of patients
 with severe sepsis and peripheral perfusion. Objective: the aim of this study is to evaluate
 the efficacy of HFNC for improving sixty-day survival in patients with severe sepsis. Design:
 multicenter parallel-group randomized clinical trial. Method: 592 adult patients with a
 diagnosis of severe sepsis in the first 12 hours of admission in the Emergency Room will be
 randomly assigned to an experimental or control group. In the experimental group, HFNC will
 be administered until the resolution of sepsis or until required mechanical ventilation,
 either invasive or non-invasive. In the Control group, conventional oxygen will be
 administered, if required. Sixty-day survival will be the primary outcome. The study is
 powered to demonstrate an improvement in survival from 70% in control group up to 80% in the
 HFNC group. The secondary outcomes will be reducing the need for vital support (mechanical
 ventilation, dialysis, vasoactive drugs) and physiological (acidosis, clearance of lactate,
 SvO2 and SOFA). Statistical analysis: Kaplan-Meier curves and Cox proportional hazard models
 will be calculated for all-cause sixty-day survival. If the results are conclusive, they will
 have immediate application in medical practice.
Severe sepsis is a syndrome associated with severe infections with a high morbidity and
 mortality. In its most severe form, septic shock still leads to an in-hospital mortality of
 up to 50%. The pathophysiology of severe sepsis / septic shock includes increased work of
 breathing to compensate for tissue hypoperfusion-induced metabolic acidosis. This exaggerated
 work of breathing requires increased consumption of oxygen by respiratory muscles, which
 calls for a greater percentage of the already insufficient cardiac output, which can
 aggravate tissue hypoperfusion.

 In the last decade, high flow nasal cannula (HFNC) appeared as an alternative ventilatory
 support intermediate between conventional oxygen and mechanical ventilation. Among others
 (3-7), the investigators have also demonstrated their effectiveness in patients with
 respiratory failure of different etiologies (8-11). Patients treated with HFNC quickly show a
 reduction of respiratory rate and respiratory work, associated with an improvement of the
 functional residual capacity and gas exchange. The absence of significant side effects and
 low cost makes HFNC especially attractive as adjunctive medical treatment in severe sepsis.

 Then, the hypothesis is that in patients with severe sepsis, high flow nasal cannula (HFNC)
 therapy could reduce work of breathing, which would allow a redistribution of cardiac output
 from the respiratory muscles to other organs, improving peripheral perfusion with minor
 injury of organs at distance, less multiorgan failure and improved survival. Therefore, the
 aim of this study is to evaluate the efficacy of HFNC for improving sixty-day survival in
 patients with severe sepsis. This study will also provide a detailed evaluation of the HFNC's
 effects on the need for vital support (mechanical ventilation, dialysis, vasoactive drugs)
 and physiological parameters (acidosis, clearance of lactate, SvO2 and SOFA).

 DESIGN Prospective, multicenter, randomized, controlled trial in 592 patients with severe
 sepsis admitted into a network of 18 ICUs from university and community hospitals in Spain to
 define the role of high flow oxygen therapy, with one experimental arm that will receive high
 flow oxygen therapy and a control arm that will receive conventional oxygen therapy if
 required.

 Patients who consent will be randomized in a 1:1 ratio to receive HFNC or conventional
 treatment, which consists of adding oxygen on nasal prongs or Venturi mask only if hypoxemia
 is detected as SpO2 < 92% by pulse oximetry.

 STUDY ARMS

 1. HFNC therapy (experimental group) Treatment with HFNC (Airvo2® Fisher & Paykel, and
 AquaNASE® Armstrong Medical) will begin with high flow (50 L/min), high temperature and
 humidity and oxygen concentration adjusted for SpO2 >92%, even with FiO2 of 0.21, if
 needed.

 The rationale for this HFNC dosage is that minute ventilation can be already reduced
 with 30 L/min, but functional residual capacity and oxygenation maximally improve at
 higher flow. On the contrary, flow >50 L/min is uncomfortable for many patients.

 In the case of clinical intolerance, flow will be reduced to 40, 30 or 20 L/min. Yet it
 is not tolerated, HFNC will be stopped and patients will receive conventional oxygen if
 required, but will be evaluated as in the HFNC group by intention to treat.

 In HFNC patients we propose an extra caution to avoid delaying a mechanical ventilation
 that would be beneficial. To do this, the ROX index (ROX = SpO2/FiO2/respiratory rate)
 will be calculated and if it is < 5, it is recommended to assess mechanical ventilatory
 support, either invasive or non-invasive.

 2. Conventional therapy (control group) Patients assigned to the conventional treatment
 will receive the standard care given at hospital which consists of adding oxygen on
 nasal prongs or Venturi mask only if hypoxemia is suggested by SpO2 < 92% by pulse
 oximetry.

 Target for oxygenation in both arms is SpO2 between 92% and 95%. SpO2 >95% without oxygen
 supply is acceptable. On the contrary, SpO2 <92% may be acceptable when needed for medical
 reasons, mainly chronic hypercapnic patients.
Inclusion Criteria:

 -  Patients > 18 yr. with diagnostic criteria for severe sepsis, within 12 hours of
 admission in the Emergency Room, defined as hypotension after hemodynamic
 resuscitation, initial lactate > 4, or persistence of organ dysfunction (oliguria <
 0.5 ml/kg/h, cyanosis, or altered consciousness).(qSOFA 1, 2 or 3)

 Exclusion Criteria:

 -  Patients who require immediate ventilatory support both invasive and non-invasive,
 defined by severe hypoxemia (PaO2/FiO2 < 150), severe tachypnea (40 x') with signs of
 respiratory fatigue or low level of consciousness (Glasgow < 8).

 -  Patients with limitation of the therapeutic effort or orders of not CPR.

 -  Patients not susceptible to treatment with HFNC (facial trauma, tracheostomized,
 rejection of previous treatments with HFNC).

 -  Participation in other clinical trials that may affect survival.

 -  Home treatment with oxygen, CPAP or Non-invasive ventilation.