1. To study the short- and long-term effect of different target PaO2's on circulatory status, organ dysfunction and outcome.2. To study underlying mechanisms of hyperoxia by determining differences in oxidative stress response between the…
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Source
Brief title
Condition
- Other condition
Synonym
Health condition
orgaandysfunctie en SIRS
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary outcome will be the cumulative delta Sequential Organ Failure
(SOFA) score in the first 14 days).
Secondary outcome
Secondary parameters will include:mean, maximum, delta SOFA score, time spent
in the assigned PaO2 range, hypoxic episodes (PaO2 <55 mmHg), vasopressor /
inotrope requirements, need for renal replacement therapy and fluid balances
(timepoint: first 14 days). Furthermore, oxidative stress parameters
F2-isoprostanes will be determined (on day 1, 2 and 4) and as clinical
endpoints: duration of mechanical ventilation, ventilator-free days, length of
stay (in ICU, in hospital) and mortality (ICU and hospital). Interim analyses
will take place after inclusion of 100 and 250 patients to detect possible
differences in mortality.
Subgroup
To further investigate the circulatory changes due to differences in oxygen
suppletion, we will study additional parameters in a subgroup of patients,
which are too time-consuming to be performed in the whole group. We will
estimate hemodynamics by PICCO (C.I., SVRI, extravascular lung water),
microcirculation by sublingual Sidestream Dark Field imaging, and body fluid
status and bio-impedance.
Background summary
Hyperoxia has been encountered in 44% of the patients requiring ventilatory
support in the Intensive Care. However, contrary to hypoxia, many physicians do
not consider hyperoxia harmful for their patients. To stay away from hypoxia,
superfluous administration of oxygen is common practice. Since the pulse
oximeter never indicates more than 100%, physicians are often not aware of the
unphysiological high PaO2 level. Hyperoxic arterial blood gas values do not
commonly cause concern, as physicians lower the FiO2 in only 25% of the
observed cases 1.
However, an increasing number of studies not only confirm the well-known
negative pulmonary effects of chronic hyperoxia, but also point to more acute
circulatory and perfusion effects. In patients with myocardial or cerebral
infarction, for example, hyperoxia increases infarct size and mortality. After
cardiac arrest, hyperoxia is associated with worse functional outcome and
increased mortality.
The underlying mechanisms of hyperoxia's detrimental effects are not clarified.
Increased production of reactive oxygen species (ROS), causing oxidative
stress, may play a pivotal role, although not all study results are
unequivocal. Both animal and human studies suggest that oxidative stress
induces systemic vasoconstriction, especially in the microcirculation with a
loss of functional capillary density and diminished microvascular flow. This in
turn augments systemic vascular resistance and impairs cardiac output. Impaired
effective circulating volume and microvascular tissue perfusion will outweigh
marginally higher arterial oxygen content (dissolved oxygen hardly contributes
to blood oxygen content). Hence, a loss of organ perfusion and oxygen delivery
may occur .
However, hyperoxia can also induce several favourable effects, illustrating the
need for more clinical and preclinical studies. In patients with severe
systemic inflammatory response syndrome (SIRS) with concomitant vasoplegia
hyperoxia-induced vasoconstriction may stabilize hemodynamics and reduce the
need for intravenous volume resuscitation and vasopressor treatment. Common
causes of SIRS in the ICU are trauma, sepsis and ischemia/reperfusion after
cardiac arrest or cardiopulmonary bypass. In patients with ischemia/reperfusion
hyperoxia-induced vasoconstriction may also exert a preconditioning effect,
decreasing myocardial damage and other organ injury. The patients with sepsis
can also benefit from the potential antimicrobacterial properties of hyperoxia,
which may also prevent new infections. Furthermore, in patients with
haemorrhage, systemic vasoconstriction due to hyperoxia may cause
redistribution of blood flow to the vital organs with amelioration of
haemorrhagic shock-induced acute kidney injury.
In critically ill patients, a recent retrospective observational study
suggested an independent association between both low and high PaO2 with
in-hospital mortality, with the nadir of mortality between the 70 and 160 mmHg.
However, such studies are subject to many forms of bias, and another
retrospective study did not confirm these results. Clearly, prospective trials
are needed to search for the optimal pO2 range.
Hence, it is not just the uncertainty of hyperoxia's untoward effects, but also
the possibility of some favourable effects that generates the need for
prospective studies.
To the best of our knowledge, no prospective clinical studies have shown
benefits of supranormal oxygen levels in any subgroup of critically ill
patients.
In this study, we will investigate two different oxygenation levels both near
to the nadir of mortality as estimated in an earlier retrospective trial, but
one being within the natural range and the other in the supranatural range. In
critically ill patients with SIRS, we will assess the effect on organ function
and circulatory parameters. We will separately analyze the predefined subgroups
sepsis, trauma/hemorrhage and post-resuscitation.
Study objective
1. To study the short- and long-term effect of different target PaO2's on
circulatory status, organ dysfunction and outcome.
2. To study underlying mechanisms of hyperoxia by determining differences in
oxidative stress response between the hyperoxic patients and the normoxemic
groups.
Study design
Single blinded, randomized, prospective clinical trial
Intervention
We will investigate 2 groups with pO2 targets both within the range of current
practice
Group 1: target PaO2 120 ± 15 mmHg (hyperoxemic)
Group 2: PaO2 75 ± 15 mmHg (normoxemic)
Study burden and risks
The risk and burden for study subjects are small. Placement of central venous
catheters and arterial cannulas are part of standard ICU care. Blood sampling
is combined with sampling for normal care of patients and will be taken from
either the arterial cannula or the central venous catheter. Since the titrated
oxygen levels administered to the patients are based on the PaO2 measured in
blood and pulse oximetry, and the oxygen levels are within the range of current
practice, we do not expose the patients to additional risk. Diaphragm
dysfunction will be quantified (and compared between groups) using
electromyography (Edi) and ultrasonography (diaphragm thickness, thickening
fraction).
De Boelelaan 1117
Amsterdam 1081 HV
NL
De Boelelaan 1117
Amsterdam 1081 HV
NL
Listed location countries
Age
Inclusion criteria
-Age *18 years
-*2 positive SIRS-criteria:
Temperature >38oC or hypothermia <36oC
Heart rate >90 bpm
Respiratory rate >20 /min or pCO2 <32 mmHg (4.3 kPa)
Number of leucocytes >12 x 109/l of <4 x 109/l of >10% bands
-Within 24 hours of admittance to the ICU
-Expected stay of more than 48 hours as estimated by the attending physician
Exclusion criteria
-Elective surgery
-carbon monoxide poisoning
-Cyanide intoxication
-Methemoglobinemia
-Sickle cell anemia
-Known severe pulmonary arterial hypertension (WHO class III or IV)
-Known severe ARDS (Berlin criteria)
-Cardiac right to left shunting
-Pregnancy
-Severe COPD (Gold class III or IV)
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2014-003468-19-NL |
| CCMO | NL50040.029.14 |