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Eur J Cardiothorac Surg 2001;19:47-53
© 2001 Elsevier Science NL
Department of Surgery and Perioperative Science, University of Ume
, Ume, Sweden
Received 18 September 2000; received in revised form 9 November 2000; accepted 10 November 2000.
Corresponding author. Heart Centre, University Hospital of Ume, S-901 85 Ume, Sweden. Tel.: +46-90-7853650; fax: +46-90-7853601
e-mail: staffan.svenmarker.us{at}v11.se
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Abstract |
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 Top Abstract 1. Introduction2. Material and methods3. Results4. DiscussionReferences |
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Key Words: Heparin • S100-beta • Blood loss • Memory • Cardiopulmonary bypass
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1. Introduction |
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TopAbstract1. Introduction2. Material and methods3. Results4. DiscussionReferences |
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This prompted us to investigate possible clinical effects comparing the two different heparin coatings in a study of cardiac surgical patients from a broad clinical perspective with emphasis on brain function.
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2. Material and methods |
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TopAbstract1. Introduction2. Material and methods3. Results4. DiscussionReferences |
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75 years, no evidence of coagulapathy or ongoing anti-coagulation therapy, aspirin medication discontinued >7 days prior to surgery, absence of neurological disorder, advanced peripheral artery disease and poor left ventricular function. The ethical committee at the University of Ume approved the study protocol.
2.1. Management of anaesthesia and intensive care
Patients were pre-medicated with flunitrazepam 1 mg, morphine 10 mg, scopolamine 0.4 mg and the normal doses of ß-blockers and nitrates. Monitoring included blood pressure from the radial artery and the right internal jugular vein, pulse oximetry, seven-lead ECG with ST-segment analysis and capnometry. Anaesthesia was maintained with fentanyl, midazolam, propofol, isoflurane and pancuronium for muscle relaxation. Postoperative ventilatory support continued until haemodynamic and respiratory conditions were stable. Preferred analgesics were ketobemidone and paracetamol, supplemented with propofol sedation. Chest drain blood was auto-transfused during the first eight postoperative hours.
2.2. Surgical technique
Surgical technique followed a standard protocol including median sternotomy, dissection of left internal mammary artery (LIMA), cannulation of aorta and the right atrium. CPB was initiated, aortic cross-clamp applied and antegrade cold crystalloid cardioplegia (St. Thomas II) was given into the aortic root. LIMA was preferably anastomosed to the left anterior descending coronary artery. Peripheral anastomoses were performed, aortic cross clamp released and central anastomoses completed behind a side-biting clamp. The patient was gradually weaned from CPB. Remaining blood in the heart-lung machine circuit was re-transfused.
2.3. Control of CPB
CPB was conducted at 34°C using a roller pump, (Sarns 9000 Perfusion System, Ann Arbor MI) set to non-pulsatile flow and adjusted to maintain a mixed venous oxygen saturation>70% (Bentley OxiSAT II, Baxter Healthcare). Mean arterial pressure (MAP) was kept >50 mmHg and central venous pressure (CVP) <10 mmHg. Acid–base balance followed an alpha-stat regime. Circuitry in the CBAS group comprised: Maxima PRF membrane oxygenator, Intersept 40 µm arterial line filter, MVR 1600 collapsible venous reservoir and Intersept CB1351 cardiotomy reservoir (Medtronic). Duraflo group: SpiralGold membrane oxygenator, AF-1 040 GOLD arterial line filter, BMR 1900 GOLD collapsible venous reservoir and CTR-3500 GOLD cardiotomy reservoir (Baxter Healthcare). Control group: brand identical non-heparin-coated components. Circuits were primed with Ringer's acetate (Kabi Pharmacia, Uppsala, Sweden) 1800 ml and mannitol (Fresinius Kabi, Uppsala, Sweden) 200 ml; and heparin 2500 IU in the CBAS and Duraflo groups, 7500 IU in the control group. Before commencing CPB, the priming solution was re-circulated through a 2-µm pre-bypass filter for at least 10 min.
Anticoagulation was achieved by administering heparin (5000 IU/ml) (Lövens Läkernedel AB, Malmö, Sweden) to meet an activated clotting time (ACT) longer than 250 s in the two heparin-coated groups and 500 s in the control group. The heparin and protamine requirements (Lövens Läkemedel) were calculated using the Hepcon HMS 500 apparatus (Medtronic HemoTec Inc., Englewood, CO). Possible remaining heparin effect was verified by a heparinase-induced ACT measurement (Medtronic HemoTec).
2.4. Evaluation of outcome
Postoperative outcome was determined by platelet count, white blood cell count (WBC), creatinine and haemoglobin concentration. Furthermore, morning body temperature on postoperative days 1–5, inotropic support, postoperative chest drain volume, homologous blood transfusions, postoperative ventilation time, length of stay in intensive care unit (ICU) and hospital (LOS). Platelet function was examined within a sub-group of the CBAS (n=18) and equivalent controls (n=18) by performing a Hemotest (Hepcon HMS, Medtronic HemoTec). Platelet activating factor (PAF) was determined on induction of anaesthesia and compared to a second sample 30 min post protamine administration.
2.5. Registration of deviations from the norm
All patients were scrutinized before leaving the ICU and at discharge from hospital by the primary nurse according to a set of predefined categories of deviations from the normal postoperative course: neurology, circulation, surgery, respiration, kidneys, infection, gastro-intenstinal tract, endocrinology, anaesthesia, pain and miscellaneous. The information was saved in the departmental database [16]. The incident rate of deviations was compared between groups.
2.6. Brain function
Explicit and implicit memory function was tested on the day before surgery, repeated after seven days or at the time of discharge. The SuperLab (Cedrus Ltd, USA) software was employed to present a series of sixty line drawings [17] on a Macintosh laptop computer. Following a short distraction, the line drawings were re-presented combined with new items inside three different tests. The first test measured implicit memory determined as the effect of priming accounting for pictures presented initially. In the two following tasks, explicit memory was determined by the ability to discriminate between picture orientation and new and old items. Test conditions were standardized and supervised by a neuro-psychologist (T.K.). A typical test session lasted 20 min.
S100B2, a brain-specific glial protein, was analysed in serum with the immunoluminometric assay LIA-mat Sangtec 100 (AB Sangtec Medical, Bromma, Sweden). Measuring range: 0.02–20 µg/l. S100 was sampled before surgery, after 60 min of and 7 h post CPB. Samples were frozen at -70°C and analysed as one batch at the laboratory for clinical chemistry, Karolinska Sjukhuset, Stockholm, Sweden. Reported coefficient of variation was 6.6%.
2.7. Memory function follow-up 4 months after surgery
A questionnaire was sent to all patients four months after discharge from hospital. The questionnaire [18] documented memory function before and after surgery determined both by the patient and by next of kin. Six specific questions on memory function graded from 1 to 5 were asked. A summation score was used for analysis.
2.8. Statistical analysis
Analysis of variance (ANOVA) was employed to determine group differences, one-way ANOVA for a single variable and ANOVA for repeated measures for a variable studied over time. Post hoc analysis was performed following a significant F-test (P<0.05). Scheffé was the preferred test for a variable with equal variances across groups. Otherwise, the Tamhane T2 test was executed. Categorical data were tabulated and differences between cell frequencies were statistically verified using Fisher's exact test. A P value of less than 0.05 was regarded as statistically significant. Results are given as mean±standard error of the mean.
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3. Results |
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TopAbstract1. Introduction2. Material and methods3. Results4. DiscussionReferences |
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The great majority of patients were easily weaned from CPB. Pharmacological support was used in 9% of the cases, with no inter-group difference (P=0.653). Intraoperative fluid balance components were similar for all groups: CPB volume (including prime) 2974±43 ml (P=0.319), urine output 957±24 ml (P=0.820), blood loss 420±9 ml (P=0.066) and haematocrit 31.8±0.3% (P=0.195). Administered anaesthetics are outlined in Table 3.
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WBC increased from (6.7±0.1x109/l) preoperatively to (13.2±0.2x109/l) at the postoperative measurement (P=0.000). At discharge the WBC was normalized (8.4±0.1x109/l) and with no apparent group difference (P=0.407). Platelet count before surgery (232±3x109/l) decreased post surgery (223±3x109/l) followed by a steep rise at time of discharge from hospital (319±6x109/l) (P=0.000) to the same extent in all groups (P=0.670). Creatinine level (100.3±1.4 µmol/l) during the ICU stay was generally considerably higher than preoperatively (87.0±0.9 µmol/l) (P=0.01), with a marked lower creatinine rise in the heparin treated groups CBAS (P=0.037) and Duraflo (P=0.015). However, no difference between the two heparin-treated groups (P=0.958) was detected. The postoperative fever reaction observed on the first postoperative day, 37.6±0.04°C, normalized similarly in all groups during the following four days: 2nd, 37.6±0.03°C; 3rd, 37.5±0.04°C; 4th, 37.5±0.03°C; 5th: 37.4±0.03°C (P=0.446).
3.3. Deviations from the norm
Proportion of patients with no observed postoperative deviation was CBAS 59.0%, Duraflo 70.0% and control 58.0% (P=0.150). Incidence of specific deviations is outlined in Table 4. Patents in the Duraflo group were associated with a lower incidence of atrial fibrillation (P=0.044).
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Ninety-five percent of the patients completed the questionnaire on memory function follow-up. Memory function as subjectively determined by the patient was clearly suppressed at four months post surgery (P=0.000). The mean preoperative value of 17.4±0.1 fell to 14.7±0.1 and somewhat more in the control group than in the other groups from 17.6±0.4 to 14.3±0.3 (P=0.021). In contrast, next of kin was not able to identify any change of memory function (17.4±0.1 to 17.6±0.2) (P=0.801).
S100 rose from a mean preoperative value of 0.00±0.00 µg/l to 0.76±0.03 µg/l after 60 min of CPB (P=0.000). Seven hours post CPB the concentration had decreased to 0.39±0.03 µg/l (P=0.000). During CPB the S100 elevation was greatest in the control group (0.89±0.07 g/l) compared with CBAS (0.65±0.05 µg/l) (P=0.026) and Duraflo (0.73±0.05 µg/l) (P=0.239). No difference was detected between the Duraflo and CBAS groups (P=0.611). Concentrations of S100 were still abnormally elevated (P=0.000) 7 h post CPB without differences between groups (P=0.762). The mean release of S100 analysed as area under the curve (32.0±1.5 µg/l per h) demonstrated a similar response in all groups (P=0.289). The response pattern of S100 to CPB is depicted in Fig. 3.
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4. Discussion |
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TopAbstract1. Introduction2. Material and methods3. Results4. DiscussionReferences |
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Looking at more specific outcome parameters, a number of research groups [4–6,10,19] have documented a reduction of blood loss when using heparin-bonded CPB. Controversies exist whether this should be attributed to the heparin surface per se or an effect of administering a reduced dose of systemic heparin [19]. We used a low-dose heparin regime and were able to reduce both blood loss and transfusion requirements in the Duraflo and CABS groups. The maximum blood-saving effect was 123 ml or 20% (Duraflo versus control). However, when comparing the pre- and postoperative haemoglobin value for patients not exposed to blood transfusion there were no differences between groups. The finding coincides with reports from other research groups [6,9]. Haemostatic disturbances following CPB involves preservation of initial clotting induced by normally functioning platelets. Interestingly, we identified a better preserved platelet function for patients in the CBAS group. This may be attributed to the heparin surface itself causing less activation [8] or exposure to lower concentrations of heparin and protamine. Gorman and colleagues investigated the effect of the CBAS coating on coagulation using an extensive set of markers. The only significant benefit identified was the improved platelet function [8]. The isolated effect of heparin coating on blood loss is debatable [8,9,15] as also is the possible additive effect of different anticoagulation strategies. Alternatively, heparin-coating characteristics vary with the systemic heparin concentration.
The safety of reducing the systemic heparin dose is controversial. Kuitunen and colleagues [14] reported a marked activation of the coagulation cascade and thrombin formation as compared to a full-dose heparin regime. Others have also made the same observation, both experimentally [12] and clinically [10]. However, activation of coagulation during CPB seems inevitable despite high doses of heparin [8] and maintaining ACT above 480 s [6,10,11,14]. Combining systemic and surface bonded heparin would logically enhance anticoagulation. Using different markers of thrombin generation, this postulated effect has been difficult to demonstrate and may question the role of surface-bound heparin [8]. What still may make the use of a low heparin dose regime justified is the modest intraoperative amplification of coagulation compared with postoperative levels as demonstrated by Øvrum and associates [10]. Increasing levels of thrombin may also be related to use of cardiotomy suction, leading to an insufficient block of the extrinsic coagulation pathway [6]. The safe use of a cardiotomy reservoir may therefore in this respect be questioned. As the world-wide experience of heparin bonded circuits and low-dose heparin management is sparse, the potential risk involved is therefore difficult to assess. Of existing documentation, the groups of Aldea [4,6] and Øvrum [10] all report successful usage of the low-dose regime in large series of patients undergoing coronary artery bypass surgery. A close registration of deviations from the norm [16] at our institution performed during the present and in a previous investigation [5] verifies these findings. In the present study, none of the included categories of deviations differed in outcome, except from the incidence of postoperative atrial fibrillation. The lower incidence observed in the Duraflo group is striking and is in agreement with the findings of Øvrum et al. [15]. The reason for the reduced incidence of atrial fibrillation remains obscure, but may possibly be explained by a less aggressive systemic inflammatory response [15]. Strangely enough, the incident rate of atrial fibrillation was not affected in the CBAS group, which is contradictory and makes the impact of heparin coating on atrial fibrillation still doubtful [6]. Nevertheless, atrial fibrillation represents a major postoperative problem, typically experienced by more than 25% of the patients. In the present study LOS was exactly 1 day longer (P=0.000) for this particular patient group.
Our previous report [5] suggesting a reduced incidence of neurological deviations and release of S100 is not consistent with results in the present study. Use of heparin coating in CPB as a way of reducing brain cell injury is therefore not very convincing. Noteworthy is the high peak concentration of S100 in the control group compared to the two heparin-coated groups, which both demonstrated a similar response pattern.
Videm and associates [3] demonstrated recently an association between central nervous dysfunction and complement activation. Reducing SIRS by means of heparin coating may therefore have an influence on the brain and its functions. If early release of S100 is reflecting SIRS, heparin coating might still play a protective role. With reference to the outcome of neurological deviations, the possible association between heparin coating in CPB and neurological injury, as suggested [5], seems, judged from the results in this repeated investigation, not very plausible. For instance, focal neurological injury would more likely be caused by an embolic event originating from the surgical field, than the trauma generated by CPB. CPB induces a time-dependent release of S100 [20]. The peak concentration has been described to reflect a non-specific damage of the brain and/or the blood–brain barrier, whereas a late second postoperative release is usually associated with a cerebral complication [20]. More recent findings have highlighted the influence of extra-cerebral sources of S100 released from fat cells in conjunction with cardiotomy suction [21]. Indeed, these new findings [21] probably disqualify the use of S100 a marker of brain cell injury in association with CPB, or cardiotomy suction has to be excluded from the experimental design. A possible net effect of heparin coating on the release of S100 is therefore difficult to define.
Cognitive dysfunction has been found to correlate with specific markers of brain injury [22]. Neuropsychological consequences of CPB have also highlighted effects on memory functions [23]. Our data are in agreement with these reports. CPB caused impairment with respect to performance in a recognition memory task, but not in the fragment completion task. This dissociation is best understood in terms of differences between explicit and implicit memory [24,25]. In addition, this impairment also corresponded to the patient's own experiences. It is of interest that this pattern of impairment mimics what is seen in anterograde amnesia, due to damage of the medial temporal lobe and the thalamus. To the best of our knowledge, this report is the first documentation of this pattern in CPB patients. Our finding may indicate that CPB causes mild injury to the very same portions of the temporal lobe and the thalamus that cause organic amnesia. We believe that this finding merits further attention. Heparin coating did not reverse the memory impairment.
In conclusion, use of heparin coating with a reduced dose of heparin seems to be safe. There was no demonstrable negative influence on memory function and neurological complications. The two types of heparin coatings, CBAS and Duraflo, produced likewise good general clinical outcomes. A blood-saving effect was shown especially in the Duraflo group.
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Acknowledgments |
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References |
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TopAbstract1. Introduction2. Material and methods3. Results4. DiscussionReferences |
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berg T. Clinical effects of the heparin coated surface in cardiopulmonary bypass. Eur J Cardiothorac Surg 1997;11(5):957-964.[Abstract]
m Holen E., Tangen G., Brosstad F., Abdelnoor M., Ringdal L.M.A., Oystese R., Istad R. Completely heparinized cardiopulmonary bypass and reduced systemic heparin: clinical and hemostatic effects. Ann Thorac Surg 1995;60:365-371.m Holen E., Tangen G., Ringdal M.A. Heparinized cardiopulmonary bypass and full heparin dose marginally improve clinical performance. Ann Thorac Surg 1996;62(4)(1):128-133.
berg T., Svenmarker S., Hohner P., Hentschel J. Routine registration of deviations from the norm in cardiac surgery: a potent clinical research tool and quality assurance measure. Eur J Cardiothorac Surg 1997;11(1):102-136.
berg T., Ronquist G., Tyden H., Ahlund P., Bergstrom K. Release of adenylate kinase into cerebrospinal fluid during open-heart surgery and its relation to postoperative intellectual function. Lancet 1982;1(8282):1139-1142.[Medline]
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