Prognostic Role of Alveolar-arterial Prognostic Role of Alveolar-arterial Oxygen Pressure Difference (AaDO2) Oxygen Pressure Difference (AaDO2)
in Acute Pulmonary Embolismin Acute Pulmonary Embolism
Hsu Jen Te Hsu Jen Te
BackgroundBackground
This study investigated the utility of This study investigated the utility of alveolar-arterial oxygen pressure alveolar-arterial oxygen pressure difference (AaDO2) in predicting difference (AaDO2) in predicting short-term prognosis of acute short-term prognosis of acute pulmonary embolism (PE).pulmonary embolism (PE).
IntroductionIntroduction
Acute pulmonary embolism (PE) has Acute pulmonary embolism (PE) has high incidence and mortality rates high incidence and mortality rates
The International Cooperative The International Cooperative Embolism Registry of 2454 patients Embolism Registry of 2454 patients reported a high 90-day all-cause reported a high 90-day all-cause mortality rate of 17.4% mortality rate of 17.4%
ICOPER: MortalityICOPER: Mortality11.4%11.4% at 2week & 17.4 at 3 months at 2week & 17.4 at 3 months
Acute Pulmonary EmbolismAcute Pulmonary Embolism
Low PaO2Low PaO2
Low PaCO2Low PaCO2
High AaDO2High AaDO2
Four processes cause arterial hypoxaemia due to Four processes cause arterial hypoxaemia due to inefficient pulmonary inefficient pulmonary gasgas exchangeexchange::
ventilation–perfusion (ventilation–perfusion (VV//QQ) ) mismatchmismatch
HypoventilationHypoventilation
diffusion limitationdiffusion limitation
true shunt.true shunt.
ABG analysis have proved ABG analysis have proved disappointing as diagnostic modalitiesdisappointing as diagnostic modalities
normal values for alveolar-arterial normal values for alveolar-arterial oxygen gradient do not exclude oxygen gradient do not exclude acute PE acute PE
hypoxemia discriminates poorly hypoxemia discriminates poorly between those with and without between those with and without acute PE. acute PE.
absence of such abnormal values of absence of such abnormal values of arterial blood gas analysis, alone or arterial blood gas analysis, alone or in combination, do not exclude PE. in combination, do not exclude PE.
Paper reviewsPaper reviews
AaDO2 has a linear correlation to AaDO2 has a linear correlation to actual perfusion defect actual perfusion defect
a sensitive indicator suggestive of a sensitive indicator suggestive of resolved emboli resolved emboli
Prospective Investigation of Pulmonary Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED) studyEmbolism Diagnosis (PIOPED) study
a linear correlation existed between a linear correlation existed between AaDO2 and AaDO2 and PE severityPE severity
pulmonary artery mean pressurepulmonary artery mean pressure, ,
the number of the number of mismatched perfusionmismatched perfusion defects defects
Our interestsOur interests
The possibility of different gradients The possibility of different gradients of AaDO2 or other artery blood gas of AaDO2 or other artery blood gas analyses can be utilized to predict analyses can be utilized to predict prognosis of acute PE prognosis of acute PE
Methods and MaterialsMethods and Materials
CMRGP 650031CMRGP 650031
Study SampleStudy Sample
This study retrospectively identified This study retrospectively identified 114 consecutive patients hospitalized 114 consecutive patients hospitalized at Chang Gung Memorial Hospital at Chang Gung Memorial Hospital (CGMH), Taiwan, between May 2001 (CGMH), Taiwan, between May 2001 and July 2003 with acute PE. and July 2003 with acute PE.
Including criteriaIncluding criteria
spiral computed tomography (CT) orspiral computed tomography (CT) or
high probability ventilation and high probability ventilation and perfusion lung scan perfusion lung scan
first arterial blood gas analysis under first arterial blood gas analysis under room air(FIO2=0.21)<24 hoursroom air(FIO2=0.21)<24 hours
Excluding criteriaExcluding criteria
low probability ventilation and perfusion low probability ventilation and perfusion lung scanlung scan
Moderate probability ventilation and Moderate probability ventilation and perfusion lung scanperfusion lung scan
Suspecting Septic emboli or tumor emboliSuspecting Septic emboli or tumor emboli
Chronic lung diseaseChronic lung disease
TreatmentTreatment
unfractionated heparin or low unfractionated heparin or low molecular weight heparin for all ptsmolecular weight heparin for all pts
Selective thrombolysis with tPA Selective thrombolysis with tPA 100mg IVF(2 hours)100mg IVF(2 hours)
Oral warfarin for all discharged pts, Oral warfarin for all discharged pts, at least 6 monthsat least 6 months
Clinical features and biochemical Clinical features and biochemical datadata
Characteristics of ptsCharacteristics of pts －－ gender, age, gender, age, duration of symptoms, underlying disease, duration of symptoms, underlying disease, and possible risk factorsand possible risk factors
Baseline biochemical dataBaseline biochemical data －－ blood urea blood urea
nitrogen, serum creatinine, troponin I, D-nitrogen, serum creatinine, troponin I, D-dimer, artery blood gas, platelet countdimer, artery blood gas, platelet count
Electrocardiography, chest X-ray and Electrocardiography, chest X-ray and echocardiography findings echocardiography findings
Artery blood gas analysisArtery blood gas analysis
AaDO2(mmHg)=150-1.25PaCO2-AaDO2(mmHg)=150-1.25PaCO2-PaO2(FIO2=0.21)PaO2(FIO2=0.21)
a/APO2=1- AaDO2/PAO2a/APO2=1- AaDO2/PAO2
[Arterial/alveolar oxygen tension ratio [Arterial/alveolar oxygen tension ratio (a/APO2)](a/APO2)]
All measurements were obtained within 24 All measurements were obtained within 24 hours prior to anticoagulant therapy hours prior to anticoagulant therapy
The The arterial/Alveolar oxygen tension ratio(a/APO2arterial/Alveolar oxygen tension ratio(a/APO2: an index of gas : an index of gas exchange applicable to varying inspired oxygen concentrations)exchange applicable to varying inspired oxygen concentrations)
Gilbert and Karetzky et al. American review of respiratory disease 1974Gilbert and Karetzky et al. American review of respiratory disease 1974
Stability of the arterial/alveolar oxygen partial pressure ratio: effects of Stability of the arterial/alveolar oxygen partial pressure ratio: effects of low ventilation/perfusion regions. low ventilation/perfusion regions.
Gilbert el al. Critical care medicine 1979Gilbert el al. Critical care medicine 1979
Clinical EndpointsClinical Endpoints
Primary endpoint: 30-day all-cause deathPrimary endpoint: 30-day all-cause death
Secondary endpoint: composite endpoint Secondary endpoint: composite endpoint of of 30-day death30-day death and in-hospital and in-hospital complications, including complications, including cardiopulmonary cardiopulmonary resuscitationresuscitation, , mechanical ventilationmechanical ventilation and and vasopressorsvasopressors for systemic arterial for systemic arterial hypotension. hypotension.
All enrolled patients were received follow-All enrolled patients were received follow-up for > 1 year. up for > 1 year.
Statistical analysisStatistical analysis
The student’s t-test for comparing continuous The student’s t-test for comparing continuous variables variables
the proportion test for categorical variables the proportion test for categorical variables
Receiver operating characteristic(ROC) analyses Receiver operating characteristic(ROC) analyses were applied to determine the high-sensitivity were applied to determine the high-sensitivity AaDO2 and a/APO2 cutoff valueAaDO2 and a/APO2 cutoff value
Multivariate Cox regression analyses were Multivariate Cox regression analyses were
employed to estimate the cumulative probability employed to estimate the cumulative probability of primary and composite endpoints of primary and composite endpoints
ResultsResults
Total 114 patientsTotal 114 patients
Only 1 patient had an AaDO2< 20 Only 1 patient had an AaDO2< 20 mmHg. mmHg.
The other 113 patients had abnormal The other 113 patients had abnormal AaDO2 values (AaDO2> 20 mmHg). AaDO2 values (AaDO2> 20 mmHg).
Table 1. Clinical characteristics, echocardiographic parameters, and Table 1. Clinical characteristics, echocardiographic parameters, and cardiac troponin I in PE survivors and patients who died at 30 days.cardiac troponin I in PE survivors and patients who died at 30 days.
Variable 30-day survival
(n=94) 30-day death (primary end
point)(N=20)
P value
Clinical characteristics
Age 62.35 ± 14.91 63.95 ± 18.12 0.676a Duration of symptoms(day) 7.78 ± 9.64 9.20 ± 14.58 0.588a Women 46(32%) 10(50%) 0.1779b Cancer 11(11%) 9(45%) 0.0002b,** Hypotension(SBP<100mmHg) 3(3%) 7(35%) <0.0001b,***
Diabetes mellitus 17(17%) 5(25%) 0.4018 b
Hypertension 26(27%) 3(15%) 0.2597 b Congestive heart failure 8(8%) 1(5%) 0.6432 b DVT 33(35%) 7(35%) 1.0000 b CAD 3(3%) 1(5%) 0.6518 b Renal insufficiency 13(14%) 6(3%) 0.1703 b Recent surgery/immobilization 12(13%) 2(10%) 0.7123 b Thrombocytopenia 18(19%) 11(55%) 0.0008 b,** Artery blood gas analysis
PaO2 57.32 55.45 0.556 a PaCO2 31.05 27.29 0.031 a,* Aa-DO2 53.60 60.17 0.062 a,#
Aa-DO2≥53 47/94(50%) 16/20(80%) 0.0143 b,*
a/APO2 0.52 0.48 0.154 a
a/APO2<0.49 36/94(38%) 13/20(65%) 0.0280 b,*
PO2/FIO2 272.94 264.05 0.556 a
Thrombolysis Tissue plasmin activator 6(6%) 1(5%) 0.8623 b Echocardiography and troponin I RVD(RV/LV≥1) 15(16%) 6(30%) 0.1428 b TnI≥0.4 ng/ml 27(28%) 17(85%) <0.0001 b,*** TnI: troponin I; RVD: right ventricular dilatation; SBP: systolic blood pressure: a: t-test, b:
proportion test, *: p<0.05, **: p<0.001, ***: p<0.0001, #: p<0.08 locates on borderline.
Table 2. Clinical characteristics, echocardiographic parameters, and Table 2. Clinical characteristics, echocardiographic parameters, and cardiac troponin I in the 30-day composite-event free group vs. the 30-cardiac troponin I in the 30-day composite-event free group vs. the 30-
day composite event groupday composite event groupVariable 30-day free of composite
end point(n=84) 30-day Composite end
point(n=30)
P value
Clinical characteristics
Age 62.21 ± 15.40 63.80 ± 15.76 0.631 a Duration of symptoms(day) 7.19 ± 9.17 10.37 ± 13.78 0.248 a Women 37(44%) 19(63%) 0.0739 b,# Cancer 9(11%) 11(37%) 0.0014 b,** Hypotension(SBP<100mmHg) 1(1%) 8(27%) <0.0001 b,***
Diabetes mellitus 14(17%) 8(40%) 0.0102 b,*
Hypertension 24(28%) 5(17%) 0.2330 b Congestive heart failure 6(7%) 3(1%) 0.2128 b DVT 33(39%) 7(23%) 0.1143 b CAD 2(2%) 2(7%) 0.1892 b Renal insufficiency 10(12%) 9(30%) 0.0234 b,* Recent
surgery/immobilization
9(11%) 5(17%) 0.3949 b
Thrombocytopenia 16(19%) 13(43%) 0.0095 b,* Artery blood gas analysis
PaO2 58.18 53.66 0.175 a PaCO2 31.04 28.59 0.105 a Aa-DO2 52.76 60.33 0.012 a,*
Aa-DO2≥53 41/84(48%) 22/30(73%) 0.0182 b,**
a/APO2 0.53 0.47 0.017 a,*
a/APO2<0.49 30/84(36%) 19/30(63%) 0.0104 b,**
PO2/FIO2 277.04 255.54 0.175 a
Thrombolysis Tissue plasmin activator 2(2%) 5(17%) 0.0029 b,* Echocardiography and troponin I RVD(RV/LV≥1) 11(13%) 10(33%) 0.0149 b,* TnI≥0.4 ng/ml 20(24%) 24(80%) <0.0001 b,*** TnI: troponin I; RVD: right ventricular dilatation; SBP: systolic blood pressure :a: t-test, b: proportion test, *: p<0.05, **: p<0.001, ***: p<0.0001, #: p<0.08 locates on borderline
30-day mortality & composite event rate30-day mortality & composite event rate
All-cause 30-day mortality was All-cause 30-day mortality was 17.5%.17.5%.
The 30-day composite event rate The 30-day composite event rate was was 26.3%.26.3%.
Parameters influences primary end pointParameters influences primary end point
CancerCancer HypotensionHypotension ThrombocytopeniaThrombocytopenia low PaCO2 levellow PaCO2 level elevated Troponin I level. elevated Troponin I level.
Additive parameters influences secondary Additive parameters influences secondary end pointend point
diabetes mellitus (DM)diabetes mellitus (DM) AaDO2 levelAaDO2 level a/APO2 levela/APO2 level renal insufficiency renal insufficiency right ventricular dilatation (RVD). right ventricular dilatation (RVD).
The analytical findings have not The analytical findings have not been publishedbeen published
Statistical analysis demonstrated Statistical analysis demonstrated that incidence of that incidence of thrombocytopeniathrombocytopenia and and renal insufficiencyrenal insufficiency were were significantly different between 30-significantly different between 30-day composite endpoint group and day composite endpoint group and 30-day composite event-free group; 30-day composite event-free group; this analytical finding has not been this analytical finding has not been published. published.
Incidence of thrombocytopeniaIncidence of thrombocytopenia
The odds ratio for 30-day mortality The odds ratio for 30-day mortality waswas 4.49 4.49 (95% CI=1.86–10.87). (95% CI=1.86–10.87).
The odds ratio for 30-day composite The odds ratio for 30-day composite endpoint was endpoint was 2.962.96 (95% CI=1.44– (95% CI=1.44–6.11). 6.11).
Figure 1. ROC curves for variable Figure 1. ROC curves for variable artery blood gas analysis.artery blood gas analysis.
Figure 2. ROC curves for AaDO2 Figure 2. ROC curves for AaDO2 and a/APO2-Rand a/APO2-R
The area for The area for a/A PO2 a/A PO2 =0.650=0.650
The area for The area for AaDO2AaDO2
=0.657=0.657
The optimal cut-off value for The optimal cut-off value for AaDO2 was 53mmHg. AaDO2 was 53mmHg.
The incidence of AaDO2≥53mmHg also The incidence of AaDO2≥53mmHg also showed a significant difference between showed a significant difference between those two groups(primary end points)those two groups(primary end points)
the positive predictive value for 30-day the positive predictive value for 30-day death was death was 25%;25%; the negative predictive the negative predictive value was as high as value was as high as 92%92%
for the secondary endpoint, the positive for the secondary endpoint, the positive predictive value of a/APO2 was predictive value of a/APO2 was 39%,39%, and and negative predictive value was negative predictive value was 83%.83%.
A prognostic cut-off value of A prognostic cut-off value of a/APO2 ratio was 0.49 a/APO2 ratio was 0.49
the positive predictive value for the positive predictive value for primary end-point was primary end-point was 26.5%,26.5%, and and negative predictive value was negative predictive value was 89%.89%.
Figure 3. Survival curves at 1 year, based on a cut-off Figure 3. Survival curves at 1 year, based on a cut-off values of AaDO2≥53mmHg vs. AaDO2<53mmHgvalues of AaDO2≥53mmHg vs. AaDO2<53mmHg
HR=3.55 HR=3.55
(95% CI=1.19–(95% CI=1.19–10.62) 10.62)
Figure 4. Composite event-free survival curves at 1 year, based Figure 4. Composite event-free survival curves at 1 year, based on cut-off values of AaDO2≥53mmHg vs. AaDO2<53mmHgon cut-off values of AaDO2≥53mmHg vs. AaDO2<53mmHg
HR=2.55HR=2.55
(95% CI=1.14–(95% CI=1.14–5.74)5.74)
DiscussionDiscussion
What is the role of AaDO2 analysis in patients What is the role of AaDO2 analysis in patients with documented pulmonary embolism?with documented pulmonary embolism?
The AaDO2 is typically used as an index of The AaDO2 is typically used as an index of gas exchange. gas exchange.
The factors influencing AaDO2 are The factors influencing AaDO2 are diffusion gradient, ventilation-perfusion diffusion gradient, ventilation-perfusion imbalance and true shunt. imbalance and true shunt.
The combination of AaDO2 and pulmonary The combination of AaDO2 and pulmonary artery pressure have been used for artery pressure have been used for classifying PE. classifying PE.
AaDO2 53mmHg≧AaDO2 53mmHg≧
high negative predictive rate high negative predictive rate
moderate positive predictive rate.moderate positive predictive rate.
Aggressive thrombolytic strategy Aggressive thrombolytic strategy should be considered for patients should be considered for patients with an AaDO2 ≥53mmHg. with an AaDO2 ≥53mmHg.
Future investigation plan Future investigation plan
AaDO2 can be used in combination AaDO2 can be used in combination with other parameters, such as with other parameters, such as hypotension, high troponin I, RVD to hypotension, high troponin I, RVD to improve the accuracy of prognosis improve the accuracy of prognosis evaluation. evaluation.
The role of a/APO2 analysis in patients The role of a/APO2 analysis in patients with documented pulmonary embolism.with documented pulmonary embolism.
Gilbert et al. (7) investigated the impact of Gilbert et al. (7) investigated the impact of fractional inspired oxygen concentration fractional inspired oxygen concentration (FIO2) on the AaDO2 gradient and a/APO2 (FIO2) on the AaDO2 gradient and a/APO2 ratio in normal subjects. ratio in normal subjects.
They demonstrated that a/APO2 provides They demonstrated that a/APO2 provides a uniform guide to gas exchange function a uniform guide to gas exchange function over the range of FIO2 used in clinical over the range of FIO2 used in clinical practice. practice.
Gilbert et al. defined the lower limit of Gilbert et al. defined the lower limit of normal for the ratio as approximately normal for the ratio as approximately 0.750.75
The The arterial/Alveolar oxygen tension ratio(a/APO2arterial/Alveolar oxygen tension ratio(a/APO2: an index of gas : an index of gas exchange applicable to varying inspired oxygen concentrations)exchange applicable to varying inspired oxygen concentrations)
Gilbert and Karetzky et al. American review of respiratory disease 1974Gilbert and Karetzky et al. American review of respiratory disease 1974
Stability of the arterial/alveolar oxygen partial pressure ratio: effects of Stability of the arterial/alveolar oxygen partial pressure ratio: effects of low ventilation/perfusion regions. low ventilation/perfusion regions.
Gilbert el al. Critical care medicine 1979Gilbert el al. Critical care medicine 1979
In the real word, blood gas analysis could be In the real word, blood gas analysis could be checked under variable FIO2checked under variable FIO2
Notably, high FIO2 can increase the Notably, high FIO2 can increase the magnitude of a true shunt and, as FIO2 is magnitude of a true shunt and, as FIO2 is increased in normal subjects, thereby increased in normal subjects, thereby increasing the AaDO2. increasing the AaDO2.
Retrospective analysis of patient data in Retrospective analysis of patient data in this study showed that many patients this study showed that many patients underwent their first blood gas analysis underwent their first blood gas analysis under varying concentrations of oxygen under varying concentrations of oxygen support in the ER. support in the ER.
a prognostic cut-off value of a prognostic cut-off value of a/APO2 ratio was 0.49 a/APO2 ratio was 0.49
Notably, a/APO2 has similar but less Notably, a/APO2 has similar but less predictive power than AaDO2 for the predictive power than AaDO2 for the short-term composite endpoint. short-term composite endpoint.
The cut-off value of a/APO2 may provide The cut-off value of a/APO2 may provide another method for another method for adjusting the impact adjusting the impact of different FIO2of different FIO2 in clinical practice. in clinical practice.
future study will require an increased future study will require an increased number of patients who were administered number of patients who were administered different oxygen ratios. different oxygen ratios.
There was conflicting result There was conflicting result about hypoxemia.about hypoxemia.
In Geneva score, hypoxemia is an important In Geneva score, hypoxemia is an important predictor of death. predictor of death.
In our study, hypoxemia was not significantly In our study, hypoxemia was not significantly different in 1st end point and 2nd end pointdifferent in 1st end point and 2nd end point
The major cause was different selection methods-The major cause was different selection methods-high risk patientshigh risk patients
In the landmark PIOPED study, only 41% of In the landmark PIOPED study, only 41% of patients with PE had a high-probability lung scan. patients with PE had a high-probability lung scan. Most patients with PE Most patients with PE (57%)(57%) had an had an intermediate-probability or low-probability scan. intermediate-probability or low-probability scan. (5) (5)
The mechanism for widening The mechanism for widening AaDO2 and hypoxemiaAaDO2 and hypoxemia..
D’Alonzo et al. concluded that hypoxemia D’Alonzo et al. concluded that hypoxemia and increased AaDO2 was explained by and increased AaDO2 was explained by large shuntslarge shunts – lung regions with low ventilation/perfusion ratios and shunting lung regions with low ventilation/perfusion ratios and shunting
due to perfusion of atelectatic areasdue to perfusion of atelectatic areas
Manier et al. had another rationale for the Manier et al. had another rationale for the mechanism of hypoxemia and increased mechanism of hypoxemia and increased AaDO2. AaDO2. －－ decreased mixed venous O2 decreased mixed venous O2
Diffusion impairmentDiffusion impairment plays only a minor plays only a minor role in the mechanism. role in the mechanism.
Thrombocytopenia has a significant role Thrombocytopenia has a significant role in acute pulmonary embolismin acute pulmonary embolism..
This phenomenon can be explained by increased This phenomenon can be explained by increased platelet consumption in cases with severe PE platelet consumption in cases with severe PE
platelet-mediated release of humoral substances, platelet-mediated release of humoral substances, including serotonin, adenosine diphosphate, including serotonin, adenosine diphosphate, prostaglandins, and thromboxane prostaglandins, and thromboxane
Several physiological responses to platelet Several physiological responses to platelet activation, such as pulmonary hypertension, activation, such as pulmonary hypertension, bronchoconstriction, and RV failure, have been bronchoconstriction, and RV failure, have been identified. identified.
Study limitationStudy limitation
sample sizesample size uncontrolled retrospective study had uncontrolled retrospective study had
a selection bias. a selection bias. According to inclusion criteria, the According to inclusion criteria, the
study group had severe PE. study group had severe PE.
ConclusionConclusion
Measurement of AaDO2 is a highly useful and Measurement of AaDO2 is a highly useful and simple measurement for predicting short-term simple measurement for predicting short-term mortality and composite events. mortality and composite events.
It has high negative predictive value and It has high negative predictive value and moderate positive predictive value for 30-day moderate positive predictive value for 30-day death and 30-day composite events.death and 30-day composite events.
Aggressive thrombolytic treatment strategies can Aggressive thrombolytic treatment strategies can be considered for patients with initial poor be considered for patients with initial poor prognostic prognostic parameter-AaDO2≥53mmHgparameter-AaDO2≥53mmHg. .
Conclusion 2Conclusion 2
This value of a/APO2 requires further This value of a/APO2 requires further study to make a clear conclusion. study to make a clear conclusion.
Thrombocytopenia was also an Thrombocytopenia was also an indicator of poor prognosis for indicator of poor prognosis for patients with acute PE patients with acute PE
一個不經意的小發現，卻帶給我們喜悅的心情一個不經意的小發現，卻帶給我們喜悅的心情
