pulmonary embolismis a major global public health concern , with an estimated 900,000 venous thromboembolic events occurring annually in the united states alone .
massive pulmonary embolism in non - surgical patients is relatively common and presents a high degree of mortality ( 25 - 65% ) . the incidence of massive intra - operative intra - cardiac or pulmonary emboli ( ic / pe ) is low but these intra - operative events have a high degree of mortality ( 68% ) .
there is a lack of outcomes - based evidence to establish guidelines for intra - operative diagnosis and management of these rare events .
current recommendations and data emanates from case reports , case series , expert opinion , and extrapolation from other patient populations , with many practitioners relying on supportive care alone .
additionally , as there is no consensus for management of intra - operative ic / pe , the utility of several diagnostic tools remains unclear .
thus , this review evaluated four commonly used diagnostic modalities under the primary end - point of in - hospital mortality to identify whether the use of more invasive modalities prior to the ic / pe event improved mortality and whether post - intervention improvements in the physiologic parameters for each modality correlated with improvement in patients outcomes . therefore , we conducted this systematic review with the primary intention of evaluating mortality outcomes for four intervention groups in the management of thrombotic ic / pe : surgical embolectomy [ 5 , 6 ] ; thrombolysis [ 2 , 7 , 8 ] ; anticoagulation [ 9 , 10 ] ; or supportive care alone .
we hypothesized that either surgical or medical thrombectomy offers survival benefit in massive intraoperative ic / pe and also evaluated the use of more invasive techniques for early detection of ic / pe along with the improvement of physiologic parameters for each modality .
to identify the relevant literature , we used computerized literature searches of the ovid and national library of medicine s pubmed databases from 1957 to january 2012 , in addition to the google scholar s database , limited to articles in or translated - to english .
the search strategy was set up using the words : pulmonary embolism , pulmonary emboli , thromboembolism , thrombosis , thrombus , embolus , intra - cardiac thrombosis , or cardiac thrombi , in combination with intra - operative , operative , or surgery .
four broad therapeutic intervention groups were selected and each of them assessed under the primary end - point of in - hospital mortality : surgical embolectomy ( encompassing both open surgical techniques and percutaneous embolectomy ) [ 5 , 6];thrombolysis ( with variability in choice of thrombolytic agent , dosing , mode of delivery , and frequency of administration ) [ 2 , 7 , 8];anticoagulation ( typically heparin , but at variable doses and duration of therapy ) [ 4 , 9 , 10 ] supportive care alone .   surgical embolectomy ( encompassing both open surgical techniques and percutaneous embolectomy ) [ 5 , 6 ] ; thrombolysis ( with variability in choice of thrombolytic agent , dosing , mode of delivery , and frequency of administration ) [ 2 , 7 , 8 ] ; anticoagulation ( typically heparin , but at variable doses and duration of therapy ) [ 4 , 9 , 10 ] supportive care alone .  
additionally , four diagnostic modalities were assessed under the primary end - point of in - hospital mortality in two different ways : whether the use of more invasive modalities prior to the ic / pe event improved mortality and whether post - intervention improvements in the physiologic parameters for each modality correlated with improvement in patients outcomes .
the four diagnostic modalities were : invasive and non - invasive monitoring of vital signs ; pulmonary artery catheter ( pac ) or central venous monitoring device ( cvp ) ; end - tidal carbon dioxide monitoring ( etco2 ) ; and trans - esophageal echocardiography ( tee ) . a subgroup analysis for thrombotic type emboli
invasive monitoring was defined as use of the pac , cvp and arterial line monitoring .
the primary end - point of mortality was used for each diagnostic and therapeutic modality .
all data were derived from case reports or case series outlined in the reference section .
inclusion criteria required that major embolic disease was present , but the diagnosis criteria were not objectively defined .
diagnosis was instead left to the discretion of the practitioner and institution , and in some cases the diagnosis was made post - mortem .
all reports for extra - operative embolic events were excluded , as were reports of emboli or thromboembolic that did not result in hemodynamic compromise or were not classified as major embolic disease by the authors .
there were 7 cases that met the above - mentioned inclusion and exclusion criteria , but were ultimately excluded because the presenting sign of ic / pe was sudden death , which did not allow for any of the four primary interventions assessed in this review to be initiated .
additionally , non - thrombotic emboli s and neoplastic related emboli s were not included in the assessment of therapeutic modalities and mortality outcome .
data were entered into a microsoft excel worksheet and transferred to a ncss datasheet version 2007 ( salt lake , ut ) .
univariate analyses of categorical data ( either binomial or multinomial ) were done using chi - squared and fisher s exact test and logistic regression to assess the impact of the four primary interventions on mortality .
odds ratios ( ors ) were reported with 95% confidence interval and pvalues less than 0.05 were considered statistically significant . for the analysis of each treatment modality , the supportive care group was used as the reference .
age was the only numerical data that was used in multivariate logistic regression as an independent factor to predict patient mortality .
the results for numerical variables were reported as mean  standard deviation and were analyzed using one - way analysis of variance ( anova ) .
data from a total of 78 cases meeting inclusion and exclusion criteria were reviewed ( table 1 ) but one case of amniotic fluid embolism and 7 patients who presented with sudden death were excluded for analysis of therapeutic intervention ( table 1 ) .
overall mortality was not statistically different between women ( 44% ) and men ( 38% ) , with 50% of patients being female ( table 1 ) .
although the number of the reported cases of intraoperative ic / pe increased over past 40 years , the mortality rate for this uncommon event has remained stable ( 40.9% ) as depicted in figure 1 . the mortality rate of intra - operative intra - cardiac or pulmonary embolism over time .
different types of emboli were not statistically significant predictors of mortality . among all the cases
reported , the thrombotic etiology ( 61.5% ) was the most common type of emboli followed by gaseous ( 17.9% ) [ 5 , 10 , 11,12,13,14,15,16,17,18,19,20,21 ] and neoplastic emboli ( 16.7% ) .
there were also two cases of fat emboli   and one case of amniotic fluid embolism   ( table 1 ) .
the mortality rates were similar among those with thrombotic and neoplastic etiologies ( 43.5% and 40.0% , respectively ) which were significantly worse than those with air embolism ( 27.3% , p<0.05 ) .
although there were reports of incidental diagnosis of ic / pe by use of tee , the preoperative use of this tool did not alter mortality .
however , the use of pac prior to the embolic event was associated with improved mortality ( or=0.3[0.1 - 0.8 ] , p=0.035 , table 1 ) . for post - intervention monitoring , improvements in physiologic parameters for each of the four diagnostic modalities correlated significantly with survival , but it is worthwhile noting that 13 - 16% patients that showed early improvement of vital signs did not survive ( table 2 ) .
mortality outcomes per improvement in post - intervention physiologic parameters . of note , to assess the efficacy of each therapeutic intervention , we excluded 7 patients who manifested with sudden cardiac death that precluded them from further treatment modality . overall , therapeutic interventions resulted in a better outcome compared to those received supportive care .
regardless of the cause of the embolus , 32 out of 47 patients ( 70% ) survived when all types of therapeutic intervention were aggregated ( e.g. , surgical embolectomy , thrombolysis or conventional anticoagulation ) while only 14 out of 31 patients ( 45% ) survived with instituting a supportive care , or=0.38[0.15 - 0.98 ] , p=0.04 .
univariate analysis of primary interventions with death as a primary outcome resulted in a lack of significantly different outcomes ( p=0.08 ) , but some striking findings should be noted . after separating the type of the interventions , 9 out of 11 patients ( 82% ) in the anticoagulation intervention group and 21 out 29 patients ( 72% ) in the surgical embolectomy group survived , compared to 2 out of 7 patients ( 29% ) in the thrombolytic group and 13 out of 23 patients ( 57% ) in the supportive care group ( table 3 ) .
however , the total number of patients was too low to provide sufficient power to show a significant difference among the groups .
since the usefulness of the therapeutic interventions examined were most relevant to thrombotic emboli through decreasing the size of the embolus by preventing clot formation or by its lysis / removal , we reexamined their effect on mortality in thrombotic subtype alone ( n=48 ) .
again , there were no significant differences in outcome among the treatment groups in comparison to supportive care ( p=0.10 ) .
we confirmed that massive intra - cardiac and pulmonary emboli are rare events in the operating room but are associated with high rates of morbidity and mortality . to our knowledge , this is the first study to provide evidence - based recommendations for management of intraoperative ic / pe .
the presence of a triad of inflammation , venous stasis and hypercoagulability promotes thrombus formation , which may in turn result in massive ic / pe . during intra - operative
period application / release of tourniquet or esmarch band has been reported to cause massive ic / pe . although no statistically significant mortality differences were identified among the intervention groups , some striking findings should not be ignored .
primarily , mortality was far greater in the thrombolytic intervention group ( 71% ) than in any of the other groups ( surgical embolectomy , 28% ; anticoagulation , 18% ; supportive care , 43% ) .
these results did not reach statistical significance because the data available from published reports resulted in an underpowered sample , but the degree of difference in mortality raises significant concerns about the safety of the use of thrombolytics for management of intraoperative ic / pe .
subsequent review of this topic with additional cases may yield adequate power to confirm this trend , but in the interim period it may be prudent for practitioners to consider thrombolysis as a therapy associated with a greater degree of mortality .
the finding that thrombolytic therapy is associated with worse outcomes contradicts recommendations from several sources , including the aha / acc guidelines for management of massive pulmonary emboli outside of the operating room environment .
this discordance of results may be because use of thrombolytics is contraindicated for patients whom have undergone recent surgery , suggesting that intraoperative use of thrombolytics may be contraindicated altogether .
the use of thrombolytics in the non - operative environment for treatment of pulmonary embolus in patients with contraindications has been assessed and has been reported to be high ( 40% ) , but included a high incidence of complications ( major bleeding in 92 of 478 patients and cerebral bleeding in 5 patients ) .
use of pac prior to the occurrence of the event significantly correlated with improvements in survival , which may be explained by allowing for early detection of changes in hemodynamic variables that would otherwise not have been monitored .
although early use of tee ( prior to the embolic event ) has improved the diagnosis of ic / pe in some cases   the routine perioperative use of this device was not associated with an improved outcome .
when intraoperative embolic events were suspected , however , tee was often initiated intraoperatively , proving to be a useful diagnostic and prognostic tool .
in addition to visualization the mass of thrombus or tumor , tee was generally felt to increase the detection of wall motion abnormalities and post - intervention improvements in right ventricular wall motion that correlated positively with improved survival . in fact , for each of the diagnostic modalities ( vital sign monitoring , etco2 monitoring , pac , and tee ) post - intervention improvements in physiological parameters were positively correlated with an improvement in survival , but it is well worth noting that 13 - 16% of patients with improvement in these parameters subsequently died .
this is cause for caution to each practitioner who might see improvement post - intervention , as there is still a high incidence of mortality for an undefined subset of patients .
as this study is a systematic review of previously published literature , it is inherently burdened with multiple limitations but , although a greater evidence grade would be preferable upon which to establish guidelines , it is currently impossible to perform a prospective randomized trial for management of massive intra - operative ic / pe .
aside from the standard limitations of a retrospective review ( publication bias , recall bias of past reports , and inconsistent data reporting ) , perhaps the most obvious limitations in this particular study were the relative infrequency of events , the lack of standardization between cases , and the relatively low level of evidence , as all data were extracted from previous case reports or series .
secondly , in a study of liver transplant patients whose procedures were complicated by pulmonary emboli and/or intra - cardiac thrombi , the authors compared subgroups and reported that pulmonary embolus alone was associated with a greater mortality rate as compared to combination pulmonary emboli and intra - cardiac thrombi .
our review did not include such a subgroup analysis evaluating the effectiveness of each intervention based on anatomical distribution of emboli or thromboemboli .
additionally , there was inter - operator variability in the technique and/or delivery of each therapeutic intervention , and the resultant variation may have significant clinical implications that can not be effectively accounted for with the current available data . in regards to diagnostic modalities , there was a lack of consistency in reporting of the use of each diagnostic tool , predisposing this study s resultant statistical analysis to reporting bias .
the use of intra - operative tee has often been reported and is thought to be an effective diagnostic modality as it has the capacity to both directly visualize an ic / pe and , indirectly , to establish cardiac strain as indirect evidence of hemodynamic compromise caused by mass effect   but its use prior to a massive embolic event was not associated with improved mortality outcomes .
amniotic fluid embolism was not analyzed in this review , which was in itself conducted under the assumption that mass effect contributes most significantly to the pathophysiology of massive intra - operative ic / pe events , but it has been postulated that immune modulatory pathways play a significant role in the pathophysiology of amniotic fluid emboli , perhaps more so than with other causes of ic / pe . hence , it would have been inappropriate to assess whether therapeutic modalities such as surgical embolectomy ( one of the four intervention groups ) result in better or worse outcomes , considering that mass excision may not be possible for amniotic fluid emboli .
prior to this review , recommendations for management of massive intra - operative ic / pe were limited to supportive care measures and analyses from data extrapolated from other patient populations . in this systematic review ,
anticoagulation and surgical embolectomy resulted favorable therapies for management of intra - operative ic / pe , while a trend toward harm from use of thrombolytic agents was noted .
when the size of the embolus is large enough to produce acute hemodynamic derangement , the surgical removal of the thrombus or tumor clearly offers early survival benefit and may decrease the mortality in the long run . of note ,
not all institutions have the capacity to do surgical embolectomy or support a patient on cardiopulmonary bypass and , for those that do , it is worth emphasizing that anticoagulation resulted in an equally good outcome in those with thrombotic emboli , without introducing the morbidity associated with cardiac surgery .
it is of further value to reemphasize that 13 - 16% of patients died despite post - intervention improvement in vital signs and other physiological measures , irrespective of the intervention utilized , and practitioners should remain vigilant in the post - intervention period as a significant as - of - yet undefined subset of patients appear to remain at higher risk for mortality .
further studies are necessary to obtain a higher level of evidence to strengthen recommendations for management of these often - catastrophic intra - operative events .
 introductionthe management of massive intra - operative embolism remains controversial . 
 our hypothesis was that either surgical or medical thrombectomy offers survival benefit in these patients.methodspublished case reports were reviewed for intra - operative intra - cardiac or pulmonary embolism and outcomes for the following four intervention groups were evaluated for mortality benefit : surgical embolectomy ; thrombolysis ; anticoagulation ; supportive care alone . 
 we also assessed whether the use of diagnostic modalities prior to each embolism event resulted in a mortality benefit and , separately , whether post - intervention improvement in physiologic parameters resulted in improvement in outcomes . 
 univariate analyses and logistic regression were performed to assess the impact of the four primary interventions on mortality , the primary outcome.resultsseventy-eight cases were reviewed and therapeutic interventions resulted in improved survival ( 70% ) compared to supportive care ( 45% ) , odds ratio=0.38[0.15 - 0.98 ] , p=0.04 . 
 univariate analysis of primary interventions with death as a primary outcome resulted in a lack of significantly different outcomes ( p=0.08 ) . 
 mortality rates were 71% in the thrombolytic ; 28% in surgical embolectomy ; 18% in anticoagulation and 43% in the supportive care groups . 
 the routine pre - event use of trans - esophageal echocardiography was not related with improved outcomes ( p=0.36 ) but the use of pulmonary artery or central venous catheters was ( p=0.035 ) . 
 post - intervention improvements in the physiologic parameters of each diagnostic modality were associated with an improvement in mortality ( p<0.05).conclusionsour data present some important trends among the intervention groups , raising significant concerns about the safety for the use of thrombolytics in the management of intra - operative embolism . 
Introduction
Methods
Results
Discussion
Conclusion