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Perioperative oxygen fraction - effect on surgical site infection and pulmonary complications after abdominal surgery: a randomized clinical trial. Rationale and design of the PROXI-Trial.

Meyhoff CS, Wetterslev J, Jorgensen LN, Henneberg SW, Simonsen I, Pulawska T, Walker LR, Skovgaard N, Heltø K, Gocht-Jensen P, Carlsson PS, Rask H, Karim S, Carlsen CG, Jensen FS, Rasmussen LS, PROXI Trial Gro - Trials (2008)

Bottom Line: A high perioperative inspiratory oxygen fraction may reduce the risk of surgical site infections, as bacterial eradication by neutrophils depends on wound oxygen tension.The secondary outcomes are: atelectasis, pneumonia, respiratory failure, re-operation, mortality, duration of postoperative hospitalization, and admission to intensive care unit.The sample size allows detection of a 33% relative risk reduction in the primary outcome with 80% power.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Anaesthesia, Centre of Head and Orthopaedics, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark. meyhoff@rh.dk

ABSTRACT

Background: A high perioperative inspiratory oxygen fraction may reduce the risk of surgical site infections, as bacterial eradication by neutrophils depends on wound oxygen tension. Two trials have shown that a high perioperative inspiratory oxygen fraction (FiO(2) = 0.80) significantly reduced risk of surgical site infections after elective colorectal surgery, but a third trial was stopped early because the frequency of surgical site infections was more than doubled in the group receiving FiO(2) = 0.80. It has not been settled if a high inspiratory oxygen fraction increases the risk of pulmonary complications, such as atelectasis, pneumonia and respiratory failure. The aim of our trial is to assess the potential benefits and harms of a high perioperative oxygen fraction in patients undergoing abdominal surgery.

Methods and design: The PROXI-Trial is a randomized, patient- and assessor blinded trial of perioperative supplemental oxygen in 1400 patients undergoing acute or elective laparotomy in 14 Danish hospitals. Patients are randomized to receive either 80% oxygen (FiO(2) = 0.80) or 30% oxygen (FiO(2) = 0.30) during surgery and for the first 2 postoperative hours. The primary outcome is surgical site infection within 14 days. The secondary outcomes are: atelectasis, pneumonia, respiratory failure, re-operation, mortality, duration of postoperative hospitalization, and admission to intensive care unit. The sample size allows detection of a 33% relative risk reduction in the primary outcome with 80% power.

Discussion: This trial assesses benefits and harms of a high inspiratory oxygen fraction, and the trial may be generalizable to a general surgical population undergoing laparotomy.

Trial registration: ClinicalTrials.gov identifier: NCT00364741.

No MeSH data available.


Related in: MedlinePlus

Trial sequential analysis excluding the trial of Pryor. Meta-analysis of the trials by Greif [13], Belda [12] and Mayzler [14], excluding the trial of Pryor [15] with a required information size of 1304 (APIS, a priori information size) based on an a priori relative risk reduction (RRR) of 33% and a type I error risk of 5% and a power of 80%. The cumulative z-curve constructed for a fixed-effect model as heterogeneity is 0% crosses both the traditional boundary (P = 0.05) after the first trial and the trial sequential monitoring boundary during the second trial. So there may be evidence for an effect of at least 33% RRR in a cumulative meta-analysis of trials investigating a high oxygen fraction when the Pryor trial is excluded when adjusting for repeated analyses of accumulating data.
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Figure 3: Trial sequential analysis excluding the trial of Pryor. Meta-analysis of the trials by Greif [13], Belda [12] and Mayzler [14], excluding the trial of Pryor [15] with a required information size of 1304 (APIS, a priori information size) based on an a priori relative risk reduction (RRR) of 33% and a type I error risk of 5% and a power of 80%. The cumulative z-curve constructed for a fixed-effect model as heterogeneity is 0% crosses both the traditional boundary (P = 0.05) after the first trial and the trial sequential monitoring boundary during the second trial. So there may be evidence for an effect of at least 33% RRR in a cumulative meta-analysis of trials investigating a high oxygen fraction when the Pryor trial is excluded when adjusting for repeated analyses of accumulating data.

Mentions: In a single trial, interim analyses increase the risk of type I error. To avoid an increase of overall type I error, monitoring boundaries can be applied to decide whether a single randomized trial could be terminated early because of the P-value being sufficiently small. Because no reason exists why the standards for a meta-analysis should be less rigorous than those for a single trial, analogous trial sequential monitoring boundaries can be applied to meta-analysis as trial sequential analysis [7-9]. The underlying assumption for this analysis is that significance testing is performed each time a new trial is published. Trial sequential analysis depends on the quantification of the required information size. Cumulative meta-analysis of trials are at risk of producing random errors, because repetitive testing of accumulating data runs the risk of random errors and the information size requirement, analogous to the sample size of a single optimally powered clinical trial, is not met. Information size calculations were based on an assumption of a plausible relative risk reduction with an a priori relative risk reduction of 33% surgical site infections. The trial sequential analysis [7] adjusting for repeated testing on accumulating data shows that we still lack sufficient information dependent of the Pryor trial [15]. If all trials were included, neither the trial sequential monitoring boundary nor the traditional boundary (P < 0.05) were crossed (Fig. 2), and the required heterogeneity adjusted information size is 5051 to reliably detect or reject a relative risk reduction of 33% with a type I error risk of 5% and a type II error risk of 20%. If the Pryor trial [15] is excluded, the cumulative meta-analysis may be conclusive adjusted for repeated significance testing in cumulative meta-analysis, as the trial sequential monitoring boundary is crossed during the second trial (Fig. 3). As this post hoc exclusion of one of the trials testing FiO2 = 0.80 vs. FiO2 = 0.35 may be biased, we therefore concluded, considering the result of the meta-analysis of all the trials, that there may still be an information gap of more than a thousand randomized patients. So we calculated that 1400 patients must be randomized and assessed to reliably confirm a detection or rejection of a 33% relative risk reduction of surgical site infections after abdominal surgery with FiO2 = 0.80 vs. FiO2 = 0.30.


Perioperative oxygen fraction - effect on surgical site infection and pulmonary complications after abdominal surgery: a randomized clinical trial. Rationale and design of the PROXI-Trial.

Meyhoff CS, Wetterslev J, Jorgensen LN, Henneberg SW, Simonsen I, Pulawska T, Walker LR, Skovgaard N, Heltø K, Gocht-Jensen P, Carlsson PS, Rask H, Karim S, Carlsen CG, Jensen FS, Rasmussen LS, PROXI Trial Gro - Trials (2008)

Trial sequential analysis excluding the trial of Pryor. Meta-analysis of the trials by Greif [13], Belda [12] and Mayzler [14], excluding the trial of Pryor [15] with a required information size of 1304 (APIS, a priori information size) based on an a priori relative risk reduction (RRR) of 33% and a type I error risk of 5% and a power of 80%. The cumulative z-curve constructed for a fixed-effect model as heterogeneity is 0% crosses both the traditional boundary (P = 0.05) after the first trial and the trial sequential monitoring boundary during the second trial. So there may be evidence for an effect of at least 33% RRR in a cumulative meta-analysis of trials investigating a high oxygen fraction when the Pryor trial is excluded when adjusting for repeated analyses of accumulating data.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2600782&req=5

Figure 3: Trial sequential analysis excluding the trial of Pryor. Meta-analysis of the trials by Greif [13], Belda [12] and Mayzler [14], excluding the trial of Pryor [15] with a required information size of 1304 (APIS, a priori information size) based on an a priori relative risk reduction (RRR) of 33% and a type I error risk of 5% and a power of 80%. The cumulative z-curve constructed for a fixed-effect model as heterogeneity is 0% crosses both the traditional boundary (P = 0.05) after the first trial and the trial sequential monitoring boundary during the second trial. So there may be evidence for an effect of at least 33% RRR in a cumulative meta-analysis of trials investigating a high oxygen fraction when the Pryor trial is excluded when adjusting for repeated analyses of accumulating data.
Mentions: In a single trial, interim analyses increase the risk of type I error. To avoid an increase of overall type I error, monitoring boundaries can be applied to decide whether a single randomized trial could be terminated early because of the P-value being sufficiently small. Because no reason exists why the standards for a meta-analysis should be less rigorous than those for a single trial, analogous trial sequential monitoring boundaries can be applied to meta-analysis as trial sequential analysis [7-9]. The underlying assumption for this analysis is that significance testing is performed each time a new trial is published. Trial sequential analysis depends on the quantification of the required information size. Cumulative meta-analysis of trials are at risk of producing random errors, because repetitive testing of accumulating data runs the risk of random errors and the information size requirement, analogous to the sample size of a single optimally powered clinical trial, is not met. Information size calculations were based on an assumption of a plausible relative risk reduction with an a priori relative risk reduction of 33% surgical site infections. The trial sequential analysis [7] adjusting for repeated testing on accumulating data shows that we still lack sufficient information dependent of the Pryor trial [15]. If all trials were included, neither the trial sequential monitoring boundary nor the traditional boundary (P < 0.05) were crossed (Fig. 2), and the required heterogeneity adjusted information size is 5051 to reliably detect or reject a relative risk reduction of 33% with a type I error risk of 5% and a type II error risk of 20%. If the Pryor trial [15] is excluded, the cumulative meta-analysis may be conclusive adjusted for repeated significance testing in cumulative meta-analysis, as the trial sequential monitoring boundary is crossed during the second trial (Fig. 3). As this post hoc exclusion of one of the trials testing FiO2 = 0.80 vs. FiO2 = 0.35 may be biased, we therefore concluded, considering the result of the meta-analysis of all the trials, that there may still be an information gap of more than a thousand randomized patients. So we calculated that 1400 patients must be randomized and assessed to reliably confirm a detection or rejection of a 33% relative risk reduction of surgical site infections after abdominal surgery with FiO2 = 0.80 vs. FiO2 = 0.30.

Bottom Line: A high perioperative inspiratory oxygen fraction may reduce the risk of surgical site infections, as bacterial eradication by neutrophils depends on wound oxygen tension.The secondary outcomes are: atelectasis, pneumonia, respiratory failure, re-operation, mortality, duration of postoperative hospitalization, and admission to intensive care unit.The sample size allows detection of a 33% relative risk reduction in the primary outcome with 80% power.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Anaesthesia, Centre of Head and Orthopaedics, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark. meyhoff@rh.dk

ABSTRACT

Background: A high perioperative inspiratory oxygen fraction may reduce the risk of surgical site infections, as bacterial eradication by neutrophils depends on wound oxygen tension. Two trials have shown that a high perioperative inspiratory oxygen fraction (FiO(2) = 0.80) significantly reduced risk of surgical site infections after elective colorectal surgery, but a third trial was stopped early because the frequency of surgical site infections was more than doubled in the group receiving FiO(2) = 0.80. It has not been settled if a high inspiratory oxygen fraction increases the risk of pulmonary complications, such as atelectasis, pneumonia and respiratory failure. The aim of our trial is to assess the potential benefits and harms of a high perioperative oxygen fraction in patients undergoing abdominal surgery.

Methods and design: The PROXI-Trial is a randomized, patient- and assessor blinded trial of perioperative supplemental oxygen in 1400 patients undergoing acute or elective laparotomy in 14 Danish hospitals. Patients are randomized to receive either 80% oxygen (FiO(2) = 0.80) or 30% oxygen (FiO(2) = 0.30) during surgery and for the first 2 postoperative hours. The primary outcome is surgical site infection within 14 days. The secondary outcomes are: atelectasis, pneumonia, respiratory failure, re-operation, mortality, duration of postoperative hospitalization, and admission to intensive care unit. The sample size allows detection of a 33% relative risk reduction in the primary outcome with 80% power.

Discussion: This trial assesses benefits and harms of a high inspiratory oxygen fraction, and the trial may be generalizable to a general surgical population undergoing laparotomy.

Trial registration: ClinicalTrials.gov identifier: NCT00364741.

No MeSH data available.


Related in: MedlinePlus