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Eur J Cardiothorac Surg 1999;15:508-514
© 1999 Elsevier Science NL

Risk factors for intracranial hemorrhage in adults on extracorporeal membrane oxygenation¹

^a Department of Thoracic and Cardiovascular Surgery, F 25 Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA
^b Transplant Center, Cleveland Clinic Foundation, Cleveland, OH, USA

Received 20 September 1998; received in revised form 18 January 1999; accepted 27 January 1999.

Corresponding author. Tel.: +1-216-445-7052; fax: +1-216-444-0777; e-mail: smedirn@cesmtp.ccf.org

	Abstract

Top Abstract Introduction Materials and methods Results Discussion Conclusions Appendix A. Indications for... Appendix B. Variables analyzed... References

 
Objective. Intracranial hemorrhage is a recognized complication in neonates and infants on extracorporeal membrane oxygenator support and various risk factors associated with this have been defined. The prevalence and risk factors associated with intracranial hemorrhage in adults on extracorporeal membrane oxygenator support are unknown and this study was performed to define these factors. Methods. A retrospective study of adults supported with extracorporeal membrane oxygenators at a single institution between January 1992 and December 1996 was performed. Age, gender, weight, body surface area, renal function, anticoagulation, coagulation variables, blood flow, arterial pressure, arterial cannulation sites, duration of support, extracranial bleeding, native cardiac function and presence of intracranial microemboli were analyzed to determine the risk factors for intracranial hemorrhage. Results. Fourteen out of 74 adults on extracorporeal membrane oxygenator support had intracranial hemorrhage (18.9%). An increased risk of intracranial hemorrhage showed a positive correlation with female gender (P=0.02, odds ratio 6.5), use of heparin (P=0.05, odds ratio 8.5), creatinine greater than 2.6 mg/dl (P=0.009, odds ratio 6.5), need for dialysis (P=0.03, odds ratio 4.3) and thrombocytopenia (P=0.007, odds ratio 18.3). Diminishing renal function and the need for dialysis were associated with increasing duration of support. Multivariable logistic regression showed female gender and thrombocytopenia, especially with platelet counts less than 50 000 cells/mm³ to be the most important predictors of intracranial hemorrhage. Intracranial hemorrhage was associated with a mortality of 92.3% compared with a mortality of 61% in those without intracranial hemorrhage (P=0.027). Conclusion. Intracranial hemorrhage is a significant complication in adults on extracorporeal membrane oxygenator support. Judicious management of anticoagulation, prevention of renal failure and aggressive correction of thrombocytopenia may help to lower the risk of intracranial hemorrhage in adults on extracorporeal membrane oxygenator support.

Key Words: Intracranial hemorrhage • Adult extracorporeal membrane oxygenation • Support

	Introduction

Top Abstract Introduction Materials and methods Results Discussion Conclusions Appendix A. Indications for... Appendix B. Variables analyzed... References

 
Extracorporeal life support with extracorporeal membrane oxygenation (ECMO) circuit is being used with increasing frequency in adults for respiratory and hemodynamic support after reports of successful use in neonatal and pediatric populations [1] [2] [3]. In adults the use of ECMO has led to specific complications unique to itself, specifically limb ischemia, oxygenator failure, pumphead thrombus and intracardiac thrombus formation [4]. Intracranial hemorrhage (ICH) is a well recognized complication of neonatal ECMO support with risk factors such as prematurity, cardiac arrest, acidosis, thrombocytopenia, the use of heparin, jugular venous cannulation and carotid artery ligation [5] [6] [7] [8] [9] [10] [11] [12]. The incidence of ICH in adults on ECMO is not well documented and the risk factors poorly understood or unknown. The purpose of this study is to determine the prevalence and risk factors of ICH in an adult population on veno–arterial ECMO support.

	Materials and methods

Top Abstract Introduction Materials and methods Results Discussion Conclusions Appendix A. Indications for... Appendix B. Variables analyzed... References

 
Between January 1992 and December 1996, 74 adult (age>17 years) patients were identified who were supported on veno–arterial ECMO for periods greater than 24 h at the Cleveland Clinic Foundation. Of these 14 (18.9%) patients developed intracranial hemorrhage (ICH) (group A) and 60 patients had no evidence of ICH (group B).

Three groups of variables were defined and analyzed for the probability of ICH between group A and group B. These are: (1) pre ECMO variables including patient demographics, antecedent events and laboratory studies, (2) variables related to the conduct of ECMO, and (3) laboratory studies and other variables during ECMO support. The breakdown of these groups and values are detailed in Appendix A and Appendix B.

Univariable and multivariable logistic regression was used to model the probability of ICH. Chi square P-values, odds ratios and their 95% confidence intervals were computed. Using the logistic regression equation, hazard functions were determined for the continuous variables and hazard curves generated to show the risk of intracranial hemorrhage. Laboratory data from pre-ECMO to post-ECMO support were studied to identify changes and the paired t-test was used to determine if these differences were statistically significant. Also the change in laboratory studies pre- and post-ECMO support were correlated with the duration of ECMO support and Pearsons' correlation co-efficients were used to identify any statistically significant relationships. P<0.05 was considered statistically significant.

The ECMO circuit was composed of a hollow fiber microporous membrane oxygenator (Maxima, Medtronics, Anaheim, CA), a centrifugal biopump (Medtronics), heat exchanger (Medtronics or Cincinnati Subzero, Cincinnati, OH), an air–oxygen blender (Sechrist Industries, Anaheim, CA) and an arterio–venous loop made 3/8''x3/22'' Tygon tubing (Norton Performance Plastics, Wayne, NJ). All blood contact surface were heparin bonded (Carmeda Bioactive Surface, Medtronics under license from Carmeda AB, Sweden). Arterial cannulae were 16F, 18F and 20F (Research Medical) and venous cannulae ranged from 16F to 28F (Research Medical). These, as well as any connectors used, were heparin bonded (Carmeda). Arterial access was through the common femoral artery (preferred) and less often through the ascending aorta. Venous access was through the common femoral vein with the long cannula threaded to the level of the right atrium (preferred) or less commonly directly through the right atrial wall. For post-cardiotomy support, every effort was made to close the chest and obtain peripheral cannulation. Since July 1994, whenever the femoral artery was cannulated, distal leg perfusion using a 10F pediatric arterial cannula into the superficial femoral artery was used to prevent extremity ischemia. If an intra aortic balloon was used prior to ECMO support, this was left in place whenever possible to provide afterload reduction, pulsatile flow and later to help in weaning the ECMO. Ventricular drainage was never used. During post-cardiotomy ECMO support, heparin was initially reversed with protamine and when mediastinal bleeding was minimal, heparin was restarted as a continuous infusion to maintain the kaolin activated clotting time at 180–200 s. In other patients, 5000 units of heparin was given intravenously prior to ECMO insertion and subsequently maintained as above. Complete blood counts, renal function, liver function and coagulation parameters were monitored every day or more often, as needed. Platelet counts were monitored every 8 h. Bleeding was treated using infusions of packed red cells, fresh frozen plasma, cryoprecipitate or platelets as necessary. Aminocaproic acid or aprotinin were not used during ECMO support. Transcranial Doppler studies were using 2 mHz probes over both middle cerebral arteries were performed to detect microemboli to the brain. Neurological status was assessed by serial clinical examination supplemented by radiological imaging and electroencephalography. Weaning from ECMO was performed by decreasing flow and observing cardiac function by transesophageal echocardiography. To completely wean off ECMO, a native cardiac index of 2.2 l/min per m², adequate oxygenation and ability to clear CO₂ had to be present. In the presence of irreversible ventricular dysfunction, determination of suitability for cardiac transplantation was ascertained and most such patients bridged to an implantable ventricular assist device. Intact neurological function and adequate function of other systems was a prerequisite for transplantation. Presence of ICH was documented in all 14 patients in group A using computed tomography and at autopsy in the 13 who died. Intracranial hemorrhage was defined as intracerebral and or intraventricular hemorrhage. Presence of subarachnoid blood alone did not constitute intracranial hemorrhage.

	Results

Top Abstract Introduction Materials and methods Results Discussion Conclusions Appendix A. Indications for... Appendix B. Variables analyzed... References

 
Patients in group A were younger (age 46.1±15.3 vs. 53.4±13.7 years in group B), had lower body surface areas (1.80±2.0 vs. 1.92±0.20 m² in group B) and had lower weights (76.4±15.3 vs. 80.2±17.2 kg in group B). Females constituted 64.3% of group A compared with 30% in group B. Overall, females were younger than males and females in group A were younger than females in group B. Female gender carried a higher risk of ICH (Table 1). Lower age and lower body surface area also showed a positive correlation with the risk of ICH (Table 1, Fig. 1 Fig. 2 ).

View larger version (16K): [in this window] [in a new window]   Fig. 1. Hazard function showing the relationship between age and the probability of intracranial hemorrhage. The dotted lines represent 95% confidence limits.

View larger version (18K): [in this window] [in a new window]   Fig. 2. Hazard function showing the relationship between the body surface area and the probability of intracranial hemorrhage. The dotted lines represent 95% confidence limits.

Not all the patients in this series were maintained on a continuous infusion of heparin during ECMO support; 92.9% (13/14) of group A patients and 58.3% (35/60) of group B patients were on heparin infusion. The use of heparin showed a positive correlation with the occurrence of intracerebral bleeding. All patients received heparin during cannulation and during attempted weaning off ECMO support. The time of occurrence of intracranial hemorrhage was impossible to determine and hence the correlation between activated clotting times (ACT) and partial thromboplastin times (PTT) to the risk of ICH was hard to demonstrate in this retrospective study. The mean ACT of group A was 201±31 versus 236±169 s for group B (P=0.55). The mean PTT in group A was 61±25 versus 56±24 s in group B (P=0.57). The reasons for not using heparin depended on the presence of continued mediastinal, ECMO site or gastrointestinal bleeding. Heparin induced anti-platelet antibodies were detected in 14.3% (2/14) of group A and 25% (15/52, missing data in eight patients) of group B patients. However, the decrease in platelet counts were more marked in group A. Hence, the significance of the antibodies is unclear. One hundred percent of group A patients and 90% of group B patients had elevated fibrin split products. Plasma fibrinogen levels were lower in group A compared with group B (202.43±74.05 vs. 312.17±181.06 mg/dl). However this did not reach statistical significance. Hepatic dysfunction in these very sick patients may also contribute to the overall coagulopathy. Prothrombin times (PT), as a marker for hepatic synthetic function, were the only liver function studies looked at. There was a tendency towards lower PT in group A (INR 1.76 vs. 1.90), but this group also had a higher bleeding rate.

Numerous microemboli can be detected to the intracranial circulation during ECMO support using transcranial Doppler studies. These seem to be increased with the arterial cannulation is in the ascending aorta. Whether these are platelet and fibrin microaggregates or microbubbles due to cavitation phenomena are unknown [13]. Six patients in group A had transcranial Doppler studies showing numerous microemboli and eight out of 19 patients studied in group B had microemboli. An association between these microemboli and ICH was not demonstrated in this study.

The incidence of extracranial bleeding (surgical site and gastrointestinal tract), left ventricular thrombus, left ventricular ejection and intracranial microemboli were higher in group A, however, these had no statistical association with the risk of ICH.

As mentioned earlier, the duration of support on ECMO, per se, was not a risk factor for ICH. However, longer support duration correlated with increasing blood urea nitrogen (BUN) and creatinine (Table 2) (worsening renal function) and thus, the need for dialysis. The risk of developing ICH was greater with a creatinine greater than 2.6 mg/dl and the need for dialysis during ECMO support (Table 1, Fig. 3 ). Thrombocytopenia showed a very strong correlation with the risk of intracranial hemorrhage with the hazard function curve showing increasing probability of ICH with decreasing platelet counts ( Fig. 4 ). The risk substantially increases with platelet counts less than 50 000 cell/mm³ and this effect was independent of gender ( Fig. 5 ). Unlike the worsening renal function with increasing duration of support, thrombocytopenia showed no correlation (Table 2) with duration of support, but abruptly dropped to low levels within 24 h of onset of ECMO support.

View larger version (18K): [in this window] [in a new window]   Fig. 3. Hazard function showing the relationship between increasing serum creatinine during ECMO support and the probability of intracranial hemorrhage. The dotted lines represent 95% confidence limits.

View larger version (18K): [in this window] [in a new window]   Fig. 4. Hazard function showing the relationship between decreasing platelet counts during ECMO support and the probability of intracranial hemorrhage. The dotted lines represent 95% confidence limits.

View larger version (18K): [in this window] [in a new window]   Fig. 5. Composite hazard function curves showing the relationship between platelet counts during ECMO support broken down by gender and the probability of intracranial hemorrhage. At platelet counts less than 50 000 cells/mm3 the risk for intracranial hemorrhage is high irrespective of gender.

The development of intracranial hemorrhage was a clinically significant event in the 14 patients and directly led to the demise of 13 patients (mortality of 92.3%). The one patient who survived was in a persistent vegetative state for 9 months and subsequently made slow recovery. In comparison, 36 patients died from group B (mortality of 61%, P=0.027), most succumbing to multisystem dysfunction.

	Discussion

Top Abstract Introduction Materials and methods Results Discussion Conclusions Appendix A. Indications for... Appendix B. Variables analyzed... References

 
Prolonged extracorporeal circulation for adult respiratory and circulatory support has been used since DeBakey's initial description in 1971. This subsequently led to the NIH sponsored multicenter, prospective randomized trial in 1975–1978. This showed an approximately 90% mortality in the conventional treatment and ECMO groups. Based on these results, adult ECMO was essentially abandoned in the late seventies [14]. However, in the field of neonatal respiratory and circulatory support, ECMO became very successful. The Extracorporeal Life Support Organisation report in 1994 showed 81% survival in 7667 neonates supported on ECMO [8]. Two prospective randomized trials in neonates have confirmed the benefits of ECMO over conventional therapy and ECMO in neonates is now considered standard therapy [15] [16]. In the mid- to late-1980s, with improvements in centrifugal pumps and oxygenators, ECMO was reintroduced into adult support by Bartlett et al. [1]. Soon other successful reports followed and adult ECMO has become more widely used for cardiopulmonary support [2] [3].

With increasing experience in neonatal and adult support, it was evident that there were many complications associated with the use of ECMO, such as mechanical failure, clot formation in the circuits, bleeding, neurologic dysfunction, renal and metabolic complications. Intracranial hemorrhage has been a major complication in neonates occurring in upto 50% of patients in some series with a 60–70% mortality [8] [10]. The risk factors for ICH in neonates on ECMO include cardiac arrest and the need for cardiopulmonary resuscitation, hypoxia, persistent acidosis, elevated lactic acid levels, the use of heparin for anticoagulation, thrombocytopenia, instability of coagulation variables, prematurity, small birth size, intracranial malformations and possibly cerebral infarcts [5] [7] [8] [9] [10] [11] [12]. In neonates the common site of arterio–venous access are the carotid arteries and internal jugular veins. Ligation of the carotid artery and the internal jugular vein are associated with increased risk of intracranial hemorrhage [6]. In adults on ECMO support, there have been descriptions of neurologic dysfunction, however, the occurrence of intracranial hemorrhage has not been studied in detail before nor have any risk factors been defined.

The exact mechanism of ICH in adults on ECMO cannot be determined from this study. The data, however, provide some interesting clues. Alteration in hemostatic parameters are likely to be significant predisposing factors. ECMO support uniformly results in thrombocytopenia, disseminated intravascular coagulation and the development of renal dysfunction alters the function of the already reduced platelet counts. This in combination with the use of anticoagulation with heparin, significantly increases the risk of ICH. This is similar to the data from the thrombolysis trials for acute myocardial infarction where the risk of ICH was increased when heparin was used with thrombolytics [17] [18]. Initially it was hoped that heparin bonded circuits would eliminate the need for anticoagulation with heparin. However, without heparin intracardiac, pumphead and catheter tip thrombi occurred [4]. Currently, heparin infusion is maintained during support once surgical bleeding has stopped.

Thrombocytopenia was a very important predictor for increased risk of ICH and this risk was continuous for decreasing platelet counts ( Fig. 4). Even when gender was entered in this equation, low platelet count remained an independent predictor for ICH. Even males tended to have high risk of ICH with low platelet counts ( Fig. 5). Heparin induced antiplatelet antibodies were seen in both groups (14.3% in group A and 28.8% in group B). However, the decrease in platelet counts were more marked in group A. Hence the significance of the antibodies is unclear.

Plasminogen inhibitors such as aminocaproic acid (Amicar) and the serine protease inhibitor aprotinin may be useful to reduce the ongoing fibrinolysis during ECMO support. Concerns over thrombus formation has limited the use of these drugs in adults on ECMO at our institution. Sensitization to aprotinin may also be a potential problem if re-exposure occurs during LVAD implantation or transplantation.

The duration of the support in this study did not correlate with the incidence of ICH, however, it was very rare that patients are on support for more than 5 days. Most of the intracranial hemorrhages occurred on the 3rd or 4th day of support. The risk of ICH was higher with worsening renal function and especially with the need for dialysis while on ECMO support. The changes in renal function did correlate with the duration of support; longer support was associated with diminishing renal function.

Experimental studies have shown changes in cerebral blood flow and oxygen metabolism with onset of ECMO support and these may be dependent on arterial, venous pressures and bypass flow rates. Increases in cerebral blood flow velocity and increased cerebral pulse width are associated with increased risk of ICH in experimental studies in neonatal lambs [19] [20]. In this study, the ECMO flow rate, mean arterial pressure or site of arterial cannulation did not predict the risk of ICH. This may, however, be due to the difficulty of correlating the exact pressure or flow rate during the actual onset of ICH in this retrospective study. Anecdotally, we have noted sudden increases in blood pressure during cardiac recovery immediately preceding changes in neurologic status leading to the discovery of ICH in two patients. Sell et al. reported that systolic pressures greater than 90 mmHg developed in 38 of 41 newborn infants treated with ECMO leading to a 44% incidence of ICH [21]. The development of a medical management protocol with hydralazine, nitroglycerin and captopril decreased the prevalence to 9%.

Transcranial Doppler in a small number of patients revealed ongoing cerebral microemboli in essentially all of them. Experimental studies have shown sausage shaped dilatations in the cerebral microcirculation in animals with microemboli and whether these can rupture and cause bleeding is a matter for conjecture [22]. It is interesting to postulate the relationship between the development of these areas of `weakness' in the microcirculation, loss of cerebral autoregulation and hypertension to the risk of intracranial hemorrhage.

It is not clear why females have a higher risk of ICH. This association was also noted in the thrombolytic trials for acute myocardial infarction [18].

Veno–veno ECMO support may potentially require less anticoagulation and thus, may be of benefit in reducing the risk of ICH in selected patients. In patients with predominantly respiratory failure, veno–veno ECMO seems to compare very favorably with veno–arterial support. In neonates veno–veno ECMO has a higher survival rate and a much lower rate of major neurological complications [23].

	Conclusions

Top Abstract Introduction Materials and methods Results Discussion Conclusions Appendix A. Indications for... Appendix B. Variables analyzed... References

 
Adult patients on ECMO support can develop intracranial hemorrhage. The most important risk factor is thrombocytopenia. The use of heparin for anticoagulation, female gender, worsening renal function with the need for dialysis also predispose toward ICH. There seems to be no effective way to prevent thrombocytopenia which seems to affect different patients to differing degrees, however, we correct platelet counts of 100 000 cells/mm³ or less by platelet transfusions. Some degree of anticoagulation is necessary during ECMO support and careful monitoring may prevent intracranial bleeding. Prevention of renal dysfunction is difficult in these very ill patients, however, early support and faster weaning or bridging to transplantation in suitable candidates may to some extent ameliorate it. Female patients may be more prone to bleeding intracranially secondary to relative hypertension and higher flows. Thus control of these may help to reduce the risk of intracranial hemorrhage.

	Footnotes

 
Presented at the 12th Annual Meeting of the European Association for Cardio-thoracic Surgery, Brussels, Belgium, September 20–23, 1998.

	Appendix A. Indications for ECMO support

Top Abstract Introduction Materials and methods Results Discussion Conclusions Appendix A. Indications for... Appendix B. Variables analyzed... References

 

Group A n (%) Group B n (%) Risk of ICH P-values Pulmonary 1 (7.1) 12 (20) 0.1 Post myocardial infarction 2 (14.3) 13 (21.7) 0.63 Post cardiotomy 6 (42.9) 18 (30) 0.29 Myocarditis/cardiomyopathy 3 (21.4) 11 (18.3) 0.33 Post heart transplant 2 (14.3) 6 (10) 0.12 Total 14 (100) 60 (100)

	Appendix B. Variables analyzed to determine the probability of intracranial hemorrhage

Top Abstract Introduction Materials and methods Results Discussion Conclusions Appendix A. Indications for... Appendix B. Variables analyzed... References

 

I. Pre-ECMO variables Group A n=14 Group B n=60 Risk of ICH P-values Patient demographics Age (years) 46.1±15.3 53.4±13.7 0.09 Female (%) 9/14 (64.3) 18/60 (30) 0.02 Age of females (years) 44.2±11.95 49.12±18.26 Age of males (years) 49.6±21.22 55.19±11.10 Weight (kg) 76.4±15.3 80.8±17.2 0.39 Body surface area (m2) 1.80±0.20 1.92±0.20 0.07 Laboratory studies Creatinine (mg/dl) 1.46±0.74 1.56±1.28 0.78 Blood urea nitrogen (mg/dl) 35.14±16.02 25.16±19.79 0.99 International normalized ratio of prothrombin times 1.37±0.55 1.78±1.29 0.34 Platelet count cells (cells/mm3) 185 643±81 046 243 836±97 279 0.05 Antecedent event Cardiac arrest (%) 3/14 (21.4) 25/60 (41.7) 0.15 II. Variables related to conduct of ECMO Group A n=14 Group B n=60 Risk of ICH P-values Arterial cannulation site Femoral artery (%) 9/14 (64.3) 45/60 (75) Ascending aorta (%) 5 (37.5) 15/60 (25) 0.56 Anticoagulation with heparin (%) 13/14 (92.9) 35/60 (58.3) 0.05 Mean arterial pressure (mmHg) 79.5±10.9 82.3±13.9 0.50 ECMO flow (l/min) 4.52±0.78 4.39±0.75 0.56 Duration of support (days) 4.71±2.12 4.1±2.73 0.39 Extracranial bleeding sites (%) 7/14 (50) 15/60 (25) 0.12 Thrombus in left ventricle (%) 1/14 (7.2) 3/60 (5) 0.76 Presence of left ventricular ejection (%) 9/14 (64.3) 35/60 (58.3) 0.73 Intracranial Microemboli (%) (data not present on 49 patients) 6/6 (100) 8/19 (42.1) Dialysis (%) 9/14 (64.3) 20/60 (33.3) 0.03 Laboratory studies during ECMO support Creatinine (mg/dl) 3.20±0.98 2.53±1.52 0.13 Blood urea nitrogen (mg/dl) 47.15±17.00 46.96±25.18 0.97 Activated clotting time (s) 201.00±31 236±169 0.55 International normalized ratio of prothrombin times 1.76±0.66 1.90±1.84 0.78 Partial thromboplastin time (s) 61±25 (n=9) 56±24 (n=26) 0.57 Fibrinogen (mg/dl) 202.43±74.05 312.17±181.06 0.82 D-Dimers>250 14/14 (100) 54/60 (90) 0.51 Platelet count (cells/mm3) 31 857±14 136 66 377±45 626 0.007

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				P. D Raymond, M. Radel, M. J Ray, A. D Hinton-Bayre, and N. A Marsh Investigation of factors relating to neuropsychological change following cardiac surgery. Perfusion, January 1, 2007; 22(1): 27 - 33. [Abstract] [PDF]

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Vigneshwar Kasirajan Nicholas G. Smedira James F. McCarthy Filip Casselman Patrick M. McCarthy Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kasirajan, V. Articles by McCarthy, P. M. Search for Related Content PubMed PubMed Citation Articles by Kasirajan, V. Articles by McCarthy, P. M.