mechanical ventilation ( mv ) provides essential life support for patients with respiratory failure . unfortunately , this life support may cause or aggravate lung injury in acute respiratory distress syndrome ( ards ) . ventilator induced lung injury caused by repeated shear stress and barotrauma can be reduced using protective lung ventilation with lower tidal volumes . the ards network study demonstrated a compelling survival advantage when using low tidal volumes rather than conventional mv in patients with acute lung injury ( ali ) or ards . this led to the reappraisal of the goals of ventilatory support , allowing some hypercapnia , in order to limit inspiratory pressures and to lower tidal volumes . many experimental studies have demonstrated increased levels of reactive oxygen - derived free radicals , with an influx of inflammatory cells , increased pulmonary permeability and endothelial cell injury with the use of a high fraction of inspired oxygen ( fio2 ) . generally a target arterial oxygen tension ( pao2 ) of > 8  kpa ( 60  mmhg ) is suggested . a canadian questionnaire study , however , found considerable variation in the attitudes , beliefs and practices of intensivists in the management of oxygen therapy . the responses suggested that most respondents believed that levels of fio2 up to 0.4 are not harmful and that this is the ideal range of fio2 when the pao2 permits . the actual response of intensivists to hyperoxia has never been studied . in this retrospective cohort study we aimed to study whether high pao2 levels lead to adjustments in ventilator settings by intensivists in a dutch academic intensive care unit ( icu ) . the academic medical center ( amc ) in amsterdam is a teaching hospital where the icu is a 32-bed  closed format department in which medical and surgical patients ( including cardiothoracic and neurosurgical patients ) are under the direct care of the icu team . the study included all arterial blood gas ( abg ) data from all mechanically ventilated patients from 2005 until 2009 . data were extracted automatically from the patient data management system ( pdms ) storage database ( metavision , imdsoft , leiden , the netherlands ) . all patients received mv with an evita4 ventilator ( drgermedical , best , the netherlands ) or a galileo ventilator ( hamilton medical , rhzns , switzerland ) . the following mv data were recorded : fio2 , measured positive end - expiratory pressure ( peep ) level , applied tidal volume ( tv ) , inspiratory : expiratory ( i : e ) ratio and mv mode . prone positioning , recruitment manoeuvres and other complementary measures that may improve oxygenation could not be explored in this database study . for every patient the last abg test was excluded because no comparison was possible with a subsequent determination . demographic data were collected from the dutch national intensive care evaluation registry and included age , height , weight and acute physiological and chronic health evaluation ( apache ) ii score . abgs were determined routinely half an hour after every mv adjustment and also when blood glucose levels were measured . they were determined more frequently in patients without a good pulse oximetric saturation signal or on high pressure mv . all abg test results were made available on the pdms and were communicated to the clinician . the predicted body weight ( pbw ) was calculated from the following formulas : in men , pbw ( kg )  =  50  +  0.91(height in centimetres    152.4 ) ; in women , pbw ( kg )  =  45.5  +  0.91(height in centimetres    152.4 ) . in order to monitor the response to a certain extent of oxygenation we categorized the abg test results into five pao2 groups : < 8  kpa ( 60  mmhg ) , 8.0110  kpa ( 6075  mmhg ) , 10.0113  kpa ( 7598  mmhg ) , 13.0116  kpa ( 98120  mmhg ) , and > 16  kpa ( 120  mmhg ) . for the purpose of this study the last group with a pao2 > 16  kpa ( 120  mmhg ) was regarded as hyperoxic . in the amc a written mv protocol is available for all icu physicians and nurses . in addition , adaptive support ventilation is used on the hamilton galileo ventilator in patients with an uncomplicated postoperative course in whom extubation is expected within 24  h. the mv protocol is based on an open lung concept . mv is typically initiated with a fio2 0.40.6 , peep 5  cmh2o and i : e ratio 1:2 , with a target pao2 higher than 10  kpa ( 75  mmhg ) . prone positioning is considered if the peep is > 10  cmh2o and fio2 is > 0.6 . the protocol suggests lowering fio2 below 0.4 with a target pao2 higher than 10  kpa ( 75  mmhg ) . in the weaning phase , patients are candidates for discontinuation of mv if fio2 is 0.4 , peep is 5  cmh2o and no signs of respiratory distress are present . manual hyperinflation is performed as part of standard airway care , after disconnection of the ventilator and after adjustment of mv settings . recommended tidal volumes are between 6 and 8  ml / kg pbw . , nurses can decrease the fio2 if the pao2 is higher than 10  kpa ( 75  mmhg ) , but all changes in fio2 have to be reported to the physician . nurses can make ventilator therapy recommendations , but unit policy mandates that all mv setting adjustments other than lowering of fio2 are ordered by physicians . during the study period no changes in the mv protocol were made . an independent samples t - test , one - way anova and the kruskal - wallis test were used as appropriate . differences with a p value < 0.05 were considered significant . the academic medical center ( amc ) in amsterdam is a teaching hospital where the icu is a 32-bed  closed format department in which medical and surgical patients ( including cardiothoracic and neurosurgical patients ) are under the direct care of the icu team . the study included all arterial blood gas ( abg ) data from all mechanically ventilated patients from 2005 until 2009 . data were extracted automatically from the patient data management system ( pdms ) storage database ( metavision , imdsoft , leiden , the netherlands ) . all patients received mv with an evita4 ventilator ( drgermedical , best , the netherlands ) or a galileo ventilator ( hamilton medical , rhzns , switzerland ) . the following mv data were recorded : fio2 , measured positive end - expiratory pressure ( peep ) level , applied tidal volume ( tv ) , inspiratory : expiratory ( i : e ) ratio and mv mode . prone positioning , recruitment manoeuvres and other complementary measures that may improve oxygenation could not be explored in this database study . the second set was then compared with the third , and so on . for every patient the last abg test was excluded because no comparison was possible with a subsequent determination . demographic data were collected from the dutch national intensive care evaluation registry and included age , height , weight and acute physiological and chronic health evaluation ( apache ) ii score . abgs were determined routinely half an hour after every mv adjustment and also when blood glucose levels were measured . they were determined more frequently in patients without a good pulse oximetric saturation signal or on high pressure mv . all abg test results were made available on the pdms and were communicated to the clinician . the predicted body weight ( pbw ) was calculated from the following formulas : in men , pbw ( kg )  =  50  +  0.91(height in centimetres    152.4 ) ; in women , pbw ( kg )  =  45.5  +  0.91(height in centimetres    152.4 ) . in order to monitor the response to a certain extent of oxygenation we categorized the abg test results into five pao2 groups : < 8  kpa ( 60  mmhg ) , 8.0110  kpa ( 6075  mmhg ) , 10.0113  kpa ( 7598  mmhg ) , 13.0116  kpa ( 98120  mmhg ) , and > 16  kpa ( 120  mmhg ) . for the purpose of this study the last group with a pao2 > 16  kpa ( 120  mmhg ) was regarded as hyperoxic . in the amc a written mv protocol is available for all icu physicians and nurses . in addition , adaptive support ventilation is used on the hamilton galileo ventilator in patients with an uncomplicated postoperative course in whom extubation is expected within 24  h. the mv protocol is based on an open lung concept . mv is typically initiated with a fio2 0.40.6 , peep 5  cmh2o and i : e ratio 1:2 , with a target pao2 higher than 10  kpa ( 75  mmhg ) . prone positioning is considered if the peep is > 10  cmh2o and fio2 is > 0.6 . the protocol suggests lowering fio2 below 0.4 with a target pao2 higher than 10  kpa ( 75  mmhg ) . in the weaning phase , patients are candidates for discontinuation of mv if fio2 is 0.4 , peep is 5  cmh2o and no signs of respiratory distress are present . manual hyperinflation is performed as part of standard airway care , after disconnection of the ventilator and after adjustment of mv settings . recommended tidal volumes are between 6 and 8  ml / kg pbw . , nurses can decrease the fio2 if the pao2 is higher than 10  kpa ( 75  mmhg ) , but all changes in fio2 have to be reported to the physician . nurses can make ventilator therapy recommendations , but unit policy mandates that all mv setting adjustments other than lowering of fio2 are ordered by physicians . during the study period no changes in the mv protocol were made . an independent samples t - test , one - way anova and the kruskal - wallis test were used as appropriate . differences with a p value < 0.05 were considered significant . a total of 148,136 abg test results were retrieved from the database , of which 126,778 were obtained during mv . these abg tests related to 5,498 mechanically ventilated patients , of whom 4,880 were first admissions . the demographic data are shown in table  1 . in 44% of the patients admission 7% were elective patients and the others were admitted after urgent surgery for bleeding or trauma . of the surgical patients almost 40% were ventilated for recovery from anaesthesia.table  1patient characteristics of the study populationcharacteristicvalueage ( years , mean    sd)61    16gender m / f ( % ) 64/36height ( cm , mean    sd)174    9actual body weight ( kg , mean    sd)78    6predicted body weight ( kg , mean    sd)67    10apache ii score ( mean    sd)19    8referring specialty ( % )  cardiothoracic surgery37  general surgery20  internal medicine12  neurosurgery11  cardiology9  other11type of admission ( % )  medical37  unplanned surgery19  planned surgery44men  =  50  +  0.91(height in centimetres    152.4 ) ; women  =  45.5  +  0.91(height in centimetres    152.4 ) patient characteristics of the study population men  =  50  +  0.91(height in centimetres    152.4 ) ; women  =  45.5  +  0.91(height in centimetres    152.4 ) the baseline ventilator settings and adjustments together with subsequent oxygenation data for all abg tests are shown in table  2 . overall , approximately 40% of the abg tests were performed during pressure - controlled mv with a median i : e ratio of 1:2 . the mean tidal volume was 7.5    2.2  ml / kg pbw . in 57% of the abg tests the pao2 was between 8 and 13  kpa ( 6098  mmhg ) , in more than 40% the pao2 was > 10  kpa ( 75  mmhg ) , and in 22% the pao2 was > 16  kpa ( 120  mmhg ) . the median interval between two successive abg tests was 166  min ( interquartile range 100258  min ) . were not changed in most patients in any of the pao2 groups.table  2oxygenation data , ventilator settings and adjustments for all abg testspao2 category ( kpa)n ( % ) pao2 ( kpa , mean    sd)fio2peep ( cmh2o)time until next abg test ( min)delta fio2delta peep ( cmh2o)delta pao2 ( kpa ) mean    sd)no decrease in fio2 or peep , n ( % ) < 84,544 ( 3.6)7.3    0.70.5 ( 0.40.61)10 ( 712)95 ( 56159)0 ( 00.1)0 ( 02)2.8    4.63,749 ( 83)8.011021,335 ( 16.8)9.2    0.60.45 ( 0.40.51)9 ( 512)143 ( 87228)0 ( 00)0 ( 00)1.5    3.217,071 ( 80)10.011345,545 ( 35.9)11.5    0.80.4 ( 0.4 0.5)8 ( 510)174 ( 108264)0 ( 00)0 ( 00)0.6    3.132,973 ( 72)13.011627,132 ( 21.4)14.4    0.90.4 ( 0.40.42)5 ( 510)181 ( 111276)0 ( 00)0 ( 00)0.4    3.418,297 ( 67)>16.0128,222 ( 22.3)20.7    6.00.4 ( 0.40.45)5 ( 510)166 ( 99261)0 ( 00)0 ( 00)2.6    6.417,527 ( 62)data are presented as medians ( interquartile range ) unless otherwise stateddelta difference between successive abg tests oxygenation data , ventilator settings and adjustments for all abg tests data are presented as medians ( interquartile range ) unless otherwise stated delta difference between successive abg tests to study the response to hyperoxia , we subcategorized the highest pao2 group ( > 16  kpa , > 120  mmhg ) based on the fio2 ( table  3 ) . in 57% of these abg tests fio2 was exactly 0.4 and 8% had fio2 < 0.4 . in only one - quarter ( 24.9% ) of the abg tests was the fio2 decreased . of the total group with a pao2 > 16  kpa ( 120  mmhg ) , at time of the successive abg test 11% had fio2 < 0.4 , with a mean successive pao2 of 18    5.9  kpa ( 135    44  mmhg ) . at the time of the successive abg test 64% had a fio2 of exactly 0.4 . in the subsequent abg test 33% had peep above 5 cmh2o . in 78% of cases with pao2 > 16  kpa ( 120  mmhg ) and fio2 < 0.41 neither fio2 nor peep was adjusted ( table  4 ) . in contrast , in most cases with pao2 > 16  kpa ( 120  mmhg ) and fio2 > 0.4 , ventilator settings were adjusted.table  3oxygenation data , ventilator settings and adjustments in subcategory with pao2 > 16  kpafio2n ( % ) pao2 ( kpa , mean    sd)peep ( cmh2o)delta fio2delta peep ( cmh2o)delta pao2 ( kpa , mean    sd)0.210.418,287 ( 65)19.8    3.65 ( 56)0 ( 00)0 ( 00)1.5    4.50.410.68,451 ( 30)21.1    5.78 ( 510)0.05 ( 0.1 to 0)0 ( 00)3.8    6.40.610.8866 ( 3)23.8    8.212 ( 1015)0.15 ( 0.2 to 0.1)0 ( 00)7.3    8.60.811.0618 ( 2)38.9    18.910 ( 515)0.3 ( 0.5 to 0.15)0 ( 00)17.4    18data are presented as medians ( interquartile range ) unless otherwise statedin 88% of this group fio2  =  0.4delta difference between successive abg teststable  4ventilator adjustments in subcategory with pao2 > 16  kpafio2decreased fio2 , n ( % ) decreased peep , n ( % ) no decrease in fio2 or peep , n ( % ) 0.210.4998 ( 6)3,090 ( 17)14,289 ( 78)0.410.64,810 ( 57)1,798 ( 21)2,994 ( 35)0.610.8715 ( 83)174 ( 20)130 ( 15)0.811.0496 ( 81)105 ( 17)114 ( 18)in 88% of this group fio2  =  0.4 oxygenation data , ventilator settings and adjustments in subcategory with pao2 > 16  kpa data are presented as medians ( interquartile range ) unless otherwise stated in 88% of this group fio2  =  0.4 delta difference between successive abg tests ventilator adjustments in subcategory with pao2 > 16  kpa in 88% of this group fio2  =  0.4 in this retrospective database study , we found that hyperoxia ( defined as pao2 > 16  kpa , 120  mmhg ) was frequently present in patients but in most cases did not lead to adjustment of ventilator settings . if the fio2 was 0.4 or lower the hyperoxia was accepted in the majority of cases . oxygen therapy has been used in the care of critically ill patients since the early years of the last century . however , from the beginning of the 1970s increasing understanding emerged that oxygen therapy can cause pulmonary toxicity . baboons were found to have progressive alveolar septal injury after exposure to 60% oxygen for 14  days and hyperoxia ( fio2 0.5 ) exacerbated lung injury in a large tidal volume model in rabbits [ 9 , 10 ] . the acute lung injury caused by hyperoxia is characterized by an influx of inflammatory cells representing an alteration in barrier properties of the alveolar capillary membrane . some work has suggested that there is an important interaction between fio2 and pulmonary free radicals potentially leading to an adverse effect on outcome in ards . more recently , li et al .   found in mice that the combined detrimental effect of oxygen and repetitive cyclic stretch results in the activation of specific independent intracellular signalling pathways , showing that hyperoxia - induced lung injury is more than free radical - mediated injury alone . despite extensive experimental evidence in animals supporting a direct injurious effect of high inspired oxygen concentrations , a small study in 12 healthy nonsmoking adults exposed to a fractional inspired oxygen concentration of 50% ( mean exposure 44  h ) showed enhanced oxidative stress and stimulation of alveolar macrophages in bronchoalveolar lavage fluid . however , to our knowledge no studies about the safety of an inspired oxygen concentration below 40% have been performed . moreover , until now no studies concerning oxygen toxicity have been conducted in critically ill patients . the fact that neither physicians nor nurses adjusted ventilator settings in the event of hyperoxia would be understandable if other clinical signs indicated deterioration of pulmonary function . in our study , however , this is a very unlikely explanation given the fact that mean pao2 in the subsequent abg test was still 18  kpa ( 135  mmhg ) . another potential but unlikely explanation would be that physicians and icu nurses prefer some level of hyperoxia because monitoring of arterial oxygenation is performed relatively infrequently . we found a median duration between abg tests of 166  min , which is equal to almost nine abg analyses per patient - day . significantly more abg samples were taken in the group with a pao2 below 8  kpa ( 60  mmhg ) . , a study found that after the implementation of a practice guideline for abg measurement , the number of tests decreased from 4.9 to 2.4 abg tests per patient - day . in a swiss study the frequency decreased after a guideline from 8.2 to 4.8 tests per patient - day . the high number of abg tests in this study may be explained by the fact that blood glucose was also measured in the blood gas analyser . in addition to frequent abg analysis , oxygen saturation is also continuously monitored transcutaneously in all our patients . .   demonstrated in a medical patient population that pulse oximetric saturation / fio2 correlates with pao2/fio2 ratios , and thus may serve as a surrogate for the follow - up of mechanically ventilated critically ill patients . thus , unnoticed hypoxaemia is unlikely to occur and there seems to be no reason for preferring some level of hyperoxia . in our study these patients may have been disconnected from the ventilator when pao2 was high and fio2 was 0.4 . however , as only abg tests were included when patients were on mechanical ventilation , this is no explanation for our findings . furthermore , some patients had a very high fio2 ( 0.811.0 ) as well as a high mean pao2 of 39  kpa ( table  3 ) . explanations for unusually high pao2 values may include dysfunctioning pulse oximetric saturation measurements leading to high fio2 , treatment for co intoxication or hyperoxygenation during or after tracheal suction . high pao2 values only led to adjustment of inspired oxygen concentration if fio2 was higher than 0.4 . our protocol mandates a target pao2 above 10  kpa ( 75  mmhg ) and suggests decreasing the fio2 to 0.21 if the pao2 is above 10  kpa ( 75  mmhg ) . furthermore , 33% of the group with pao2 > 16  kpa ( 120  mmhg ) still had peep above 5 cmh2o in the subsequent abg test . previous reports from our institution show that feedback and education improve physician compliance in the use of lung - protective mv . it seems very likely that feedback , education and adjusted protocols concerning oxygenation will improve the weaning to a minimal fio2 of 0.21 and minimal peep level . apparently , physicians and nurses do not consider hyperoxia as potentially hazardous if fio2 is lower than 0.41 and do not adjust ventilator settings in these circumstances . interestingly , in a questionnaire study from 1999 , similar attitudes were reported among canadian intensivists . whereas high oxygen saturation measurements would urge intensivists to lower fio2 in almost all cases when fio2 was higher than 0.4 , only 54% of respondents would alter oxygen administration if fio2 was lower than 0.4 . our study is the first to reveal adjustments of ventilator settings by intensivists and icu nurses in the event of hyperoxia in intensive care patients . the main limitation of this study was the fact that it was a single - centre study . we do not know whether responses to hyperoxia are the same in other icus in the netherlands or other countries . another limitation of this study is that the clinical condition of the patient may influence decisions to change ventilator settings and that no information on the condition of the patients was available for this analysis . also , we do not know whether hyperoxia is detrimental in critically ill patients , e.g. by increasing the severity of lung injury . hyperoxia was frequently present in icu patients but in most cases did not lead to adjustment of ventilator settings . if fio2 was 0.4 or lower the hyperoxia was accepted in the majority of cases . further research is needed concerning the effects of frequently encountered hyperoxia in icu patients . for now and given the experimental evidence of hyperoxia - induced damage , it seems wise to emphasize in guidelines that hyperoxia should be limited to what is needed to ensure adequate tissue oxygenation .
purposehyperoxia may induce pulmonary injury and may increase oxidative stress . in this retrospective database study we aimed to evaluate the response to hyperoxia by intensivists in a dutch academic intensive care 
 unit.methodsall arterial blood gas ( abg ) data from mechanically ventilated patients from 2005 until 2009 were extracted from an electronic storage database of a mixed 32-bed intensive care unit in a university hospital in amsterdam . 
 mechanical ventilation settings at the time of the abg tests were retrieved.resultsthe results of 126,778 abg tests from 5,498 mechanically ventilated patients were retrieved including corresponding ventilator settings . in 28,222 ( 22% ) of the abg 
 tests the arterial oxygen tension ( pao2 ) was > 16  kpa ( 120  mmhg ) . in only 25% of the tests with pao2 > 16  kpa ( 120  mmhg ) was the fraction of inspired oxygen ( fio2 ) decreased . 
 hyperoxia was accepted without adjustment in ventilator settings if fio2 was 0.4 or lower.conclusionhyperoxia is frequently seen but in most cases does not lead to adjustment of ventilator settings if fio2 < 0.41 . 
 implementation of guidelines concerning oxygen therapy should be improved and further research is needed concerning the effects of frequently encountered hyperoxia .