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Ann Thorac Surg 1998;65:1335-1341
© 1998 The Society of Thoracic Surgeons

Effect of Nitric Oxide Gas on Platelets During Open Heart Operations

Karin Mellgren, MD, PhDa, Gösta Mellgren, MD, PhDa, Stefan Lundin, MD, PhDb, Åke Wennmalm, MD, PhDa, Hans Wadenvik, MD, PhDb

a Departments of Pediatrics, and Anesthesiology, Sahlgrenska University Hospital, Göteborg University, Göteborg, Sweden
b Departments of Anesthesiology, Pediatric Surgery, Clinical Physiology, and Medicine, Sahlgrenska University Hospital, Göteborg University, Göteborg, Sweden

Accepted for publication December 24, 1997.

Address reprint requests to Dr Mellgren, Department of Pediatrics, Sahlgrenska University Hospital/Östra, Göteborg University, S-416 85, Göteborg, Sweden


   Abstract
Top
 Footnotes
 Abstract
Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 
Background. The increased bleeding tendency observed after cardiopulmonary bypass is caused in part by thrombocytopenia and impaired platelet function induced by the procedure. Previous in vitro studies have shown that nitric oxide (NO) added to the oxygenator sweep gas reduces platelet activation during experimental perfusion. We evaluated the effect of 40 ppm of NO, added to the oxygenator sweep gas, on platelet consumption and activation in patients undergoing cardiopulmonary bypass.

Methods. Twenty patients scheduled to undergo cardiopulmonary bypass were randomized to either the control or the NO arm of the study. Their platelet count, plasma ß-thromboglobulin level, platelet membrane glycoprotein Ib and IIb/IIIa levels, adenosine diphosphate–induced platelet aggregation, plasma nitrate level, and plasma hemoglobin were assayed before, during, and after cardiopulmonary bypass.

Results. After operation, slightly higher platelet counts were observed in the NO-treated patients than in the control patients, which might indicate a lower degree of platelet adhesion to the artificial surfaces of the extracorporeal circuit. However, this difference did not reach statistical significance. In addition, a difference in platelet membrane expression of glycoprotein Ib was seen between the NO and control groups after operation; the platelets of the control patients had significantly higher glycoprotein Ib expression than those of the NO-treated patients. The results of platelet aggregometry indicated preserved platelet function in both the NO-treated and control patients. The blood methemoglobin levels also were low in both groups.

Conclusions. Nitric oxide might reduce the platelet consumption encountered during cardiopulmonary bypass without having any adverse effect on platelet function, as reflected by the preserved aggregation response seen in our patients. However, the best route of NO administration and the optimum dose remain to be established.


   Introduction
Top
 Footnotes
 Abstract
 Introduction
Material and methods
 Results
 Comment
 Acknowledgments
 References
 
Hemorrhage is still a major complication in patients treated with extracorporeal circulation. The increased bleeding tendency in these patients is due in part to impairment of platelet function after interaction with the artificial surfaces of the extracorporeal circulation system [1–3]. Drugs such as dipyridamole [4, 5], aprotinin [6], and prostacyclin [7–9] have been used during extracorporeal circulation to prevent activation and loss of platelets. However, the use of these drugs often is limited by their systemic effects. Therefore, selective and reversible inhibition of platelet activation during blood passage through the extracorporeal circuit seems to be more rational.

It is well recognized that nitric oxide (NO) inhibits platelet adhesion and aggregation [10, 11]. Nitric oxide donors (eg, nitroglycerin) have been used experimentally to decrease the platelet activation encountered during percutaneous transluminal coronary angioplasty [12] and to decrease platelet adhesion to exposed subendothelium after balloon angioplasty [13]. Nitric oxide, 550 ppm, also has been added to the oxygenator sweep gas in pigs undergoing cardiopulmonary bypass (CPB) [14] to reduce consumption. In a previous in vitro study, we observed that NO, added to the oxygenator sweep gas during a 24-hour in vitro perfusion experiment, prevented platelet activation and consumption [15]. In addition, Keh and co-workers [16], using in vitro CPB circuits, reported reduced platelet trapping in the oxygenator after the addition of gaseous NO to the gas compartment of the oxygenator.

The objective of the present study was to evaluate the effect of NO in a clinical setting. Nitric oxide was added to the oxygenator sweep gas during operations with CBP and its effect on platelet number, platelet activation, and platelet aggregation response was studied.


   Material and methods
Top
 Footnotes
 Abstract
 Introduction
 Material and methods
Results
 Comment
 Acknowledgments
 References
 
Experimental design
After the study was approved by the local ethical committee, informed consent was obtained from 20 patients (mean age, 68 years; range, 55 to 73 years) scheduled to undergo coronary bypass grafting or valve replacement operations. Ten patients were randomized to an experimental group in which NO, mixed in N2 (1,000 ppm; AGA gas AB, Lidingö, Sweden), was administered at a final concentration of 40 ppm, through Y-connector, directly to the oxygenator during the entire period of extracorporeal perfusion. This NO concentration previously has been shown to have a protective effect on platelets during in vitro experimental circulation [15]. The flow of NO gas was regulated by a flow meter (Nominus M; Dansjö Medical AB, Järfälla, Sweden). Nitric oxide and NO2 concentrations in the sweep gas were recorded by a fuel cell technique (City Technology, London, UK), immediately ahead of and after the oxygenator. The remaining 10 patients served as a control group.

The male-to-female ratio was 4-to-6 in the control group and 8-to-2 in the NO group. The mean patient age was 69 ± 3 years in the control group and 73 ± 5 years in the NO group. In the NO group, 9 patients underwent coronary artery bypass grafting and 1 patient underwent a valve operation. In the control group, 5 patients underwent coronary artery bypass grafting, 3 patients underwent valve operations, and 2 patients underwent coronary artery bypass grafting plus a valve operation. The mean CPB time was 73 ± 5 minutes in the NO-treated patients and 80 ± 8 minutes in the control patients.

Anesthesia was performed according to a standardized protocol used in our hospital, with the exception that all nitrovasodilating drugs were excluded. All patients were premedicated with flunitrazepam (1 mg), morphine (10 mg), and scopolamine (0.4 mg). Anesthesia was induced with thiopental (3 to 5 mg/kg), fentanyl (5 to 10 µg/kg), and pancuronium (100 µg/kg). Anesthesia was maintained with oxygen/nitrous oxide (40%/60%), with the addition of inhaled anesthetics. During CPB, anesthesia was maintained with a propofol infusion (150 to 300 mg/h). Patients in need of nitrovasodilators were excluded from the study, as were patients receiving aprotinin.

The operations were performed through a midline sternotomy. Heparin chloride was injected before cannulation of the aorta and right atrium. Additional heparin chloride was administered when the activated clotting time fell below 400 seconds. In all cases, the extracorporeal circulation was performed using a Safe II hollow-fiber oxygenator (Polystan, Ballerup, Denmark), a roller pump (Jostra, Hirrlingen, Germany), and the Cobe adult tubings (Gambro, Lund, Sweden). The oxygenator was primed with 1,700 mL of electrolyte solution and 200 mL of mannitol. Bypass flow was held between 3.5 and 5.5 L/min. Systemic hypothermia of 32.5° to 34.5°C was maintained during the period of aortic clamping.

Myocardial preservation during aortic occlusion was maintained with oxygenated crystalloid cardioplegia solution at 4°C injected into the aortic root. In one of the control patients, blood cardioplegia was used. After rewarming to 37°C, the patients were weaned from CPB and decannulated, and the residual heparinization was reversed with protamine sulfate (1 mg/100 IU of total heparin administered). Arterial blood samples were obtained from a peripheral arterial line (not heparinized) at the following time points: (1) before anesthesia, (2) immediately before the start of extracorporeal circulation and after heparinization, (3) after 10 minutes of extracorporeal circulation, (4) after 30 minutes of extracorporeal circulation, (5) at the end of the operation, and (6) at 3 hours after the operation.

Blood cell counting
The platelets were enumerated using an automatic blood cell analyzer (Technicon H2; Bayer, Germany).

Platelet membrane glycoproteins
Five milliliters of blood was collected into Diatube H collecting tubes (Diagnostica Stago, Leuven, Belgium) containing a platelet inhibitor cocktail provided by the manufacturer (citrate, theophylline, and adenosine). The anticoagulated blood was centrifuged at 150 g for 10 minutes to obtain a platelet-rich plasma (PRP). Twenty milliliters of PRP was incubated with a saturating concentration of fluorescein-conjugated murine monoclonal antibodies specific for glycoprotein (GP) Ib and GPIIIa (clones AN51 and Y2/51, respectively; Dakopatts, Glostrup, Denmark). After incubation for 1 hour in the dark, the samples were diluted to 1 mL and fixed with 1% paraformaldehyde.

The specimens obtained at the different sampling points were analyzed simultaneously on a flow cytometer (FACScan; Becton Dickinson Immunocytometry Systems, Mountain View, CA) equipped with a 15-mW argon ion laser. The immunofluorescence was detected through a 530/30-nm band-pass filter. A logarithmic amplifier was used for the fluorescence signal and the light scatter, and 10,000 ungated events were collected. The data were analyzed using the Lysys II software (Becton Dickinson). Gating of the list mode files first was performed using forward and side scatter to identify platelets. The fluorescence intensity of fluorescein isothiocyanate–conjugated antibody binding was obtained on platelets within these gates, and the results were expressed as median fluorescence intensity. An irrelevant fluorescein isothiocyanate–conjugated monoclonal antibody was used as a negative control.

Plasma ß-thromboglobulin
Five milliliters of blood was collected into Diatube H collecting tubes (Diagnostica Stago, Asnières-sur-Seine, France) and incubated on ice for 15 minutes. The anticoagulated blood then was centrifuged at 10,000 x g and 4°C for 30 minutes to obtain a platelet-poor plasma (PPP). The midportion of the PPP was removed and stored at -70°C. The plasma concentration of ß-thromboglobulin (BTG) was measured using a commercially available enzyme-linked immunosorbent assay (Asserachrom; Diagnostica Stago). Before assay, the PPP was diluted (1/400 to 1/800) with 0.01 mol/L of phosphate-buffered saline solution containing 3% bovine serum albumin.

Platelet aggregation
Adenosine diphosphate–induced platelet aggregation was evaluated turbidometrically according to current principles using a dual-channel platelet aggregometer (Payton Associated Limited, Stouffville, Ontario, Canada). Nine parts of blood were mixed with one part of 3.8% trisodium citrate in a plastic tube. Platelet-rich plasma and PPP were obtained by centrifugation of the anticoagulated blood at room temperature for 10 minutes at 180 g and for 20 minutes at 2,000 g, respectively. In each case, the platelet count in the PRP was determined and, if needed, PPP was added so that the platelet count in the PRP was always in the range of 100 to 200 x 109/L. The aggregation studies were performed at 37°C in a cuvette at a stirring speed of 900 rpm. The aggregation was induced by adding to 0.45 mL of PRP, 0.05 mL of physiologic saline with three different concentrations of adenosine diphosphate (Sigma Chemical Co, St. Louis, MO), giving final concentrations of 0.5 to 4.0 µmol/L. The light transmission was set at 0% with PRP and 100% with PPP. The results were interpreted as the rate of aggregation, given by a tangent to the steepest part of the aggregation curve, and as the transmission maximum [17].

Plasma hemoglobin
Five milliliters of blood was collected into heparinized tubes and centrifuged at 2,000 g for 20 minutes to obtain plasma. The plasma samples were stored at -70°C until assay. For analysis, 0.2 mL of plasma was added to 0.4 mL of 32-mmol/L dicarboxidine (Kabi AB, Uppsala, Sweden), followed by the addition of 0.2 mL of 0.2-mol/L hydrogen peroxide solution (Merck, Darmstadt, Germany), and incubated for 40 minutes. Thereafter, 4.2 mL of 3.5-mol/L acetic acid (Analar; BDH Chemical Ltd, Poole, UK) was added; after incubation for 7 minutes, the absorbance was recorded in a spectrophotometer at 450 nm. Hemoglobin solutions (10 to 100 mg/L) were used to construct a standard curve [18].

Plasma nitrate
Blood was collected in heparinized tubes and centrifuged rapidly to obtain plasma. Plasma nitrate (NO3-) was determined with a stable isotope (Na15NO3) dilution assay, using positive ion/chemical ionization gas chromatography/mass spectrometry, after conversion of endogenous and radiolabeled nitrate in the samples to nitrotoluene. This method has been described in detail elsewhere [19].

Methemoglobin
The methemoglobin concentration in the blood was recorded by an automatic blood gas analyzer (ABL 505; Radiometer, Denmark).

Statistical analysis
Standard statistical methods were used to calculate mean values and standard error of the mean. Unless otherwise stated, the mean value plus or minus the standard error of the mean is reported. Between-group comparisons were performed by the two-way analysis of variance. A p value of less than 0.05 was considered statistically significant.


   Results
Top
 Footnotes
 Abstract
 Introduction
 Material and methods
 Results
Comment
 Acknowledgments
 References
 
An instant decrease in the platelet count was seen in both the NO-treated and control patients when the extracorporeal circulation was started. At 10 minutes of CPB, the mean platelet counts recorded in the NO-treated and control patients were 61.4% ± 3.4% and 55.2% ± 2.4%, respectively, of the mean baseline values (194 ± 16 x 109/L and 178 ± 10 x 109/L, respectively) (Fig 1). At all time points studied, a small but consistent difference in normalized platelet counts, in favor of the NO-treated patients, was recorded between the two groups. At the end of the operation, mean normalized platelet counts were 74.1% ± 1.8% and 65.6% ± 3.7% of the baseline values in the NO and control groups, respectively. Even at 3 hours after the operation, the platelet count was higher in the patients who had received NO compared with the control patients: 91.6% ± 3.5% and 81.6% ± 4.2% of the baseline values, respectively. This difference in normalized platelet counts was not statistically significant (p = 0.15 by analysis of variance, treatment x time effect).



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  		Fig 1. Platelet counts in the control and nitric oxide (NO) groups during cardiopulmonary bypass (CPB). The values are given as the mean plus or minus the standard error of the mean and were normalized to the values obtained before anesthesia. The difference between the two study groups was not statistically significant.

 
Plasma levels of BTG increased significantly during the operation (Fig 2). In the NO-treated patients, the mean BTG levels recorded at baseline, at 30 minutes of CPB, and at the end of the operation were 46.8 ± 5.0 IU/mL, 77.2 ± 8.9 IU/mL, and 116.7 ± 6.4 IU/mL, respectively. In the control patients, the corresponding levels were 59.4 ± 9.6 IU/mL, 83.7 ± 9.6 IU/mL, and 129.4 ± 3.7 IU/mL, respectively. No statistically significant difference in plasma BTG levels was observed between the NO and control groups.



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  		Fig 2. Plasma ß-thromboglobulin (BTG) levels in the control and nitric oxide (NO) groups during cardiopulmonary bypass (CPB). The values are given as the mean plus or minus the standard error of the mean. No statistically significant difference was observed between the two study groups.

 
In the NO group, the membrane expression of GPIb decreased slightly during the time on CPB. After 30 minutes of CPB, the GPIb expression recorded was 95.6% ± 6.9% of the baseline value (median fluorescence intensity, 471.3 ± 62.1). In the control group, the platelet membrane expression of GPIb increased significantly during the period of CBP. The mean platelet membrane GPIb at 30 minutes of CBP was 160.7% ± 15.4% of the baseline value (median fluorescence intensity, 509.2 ± 32.8) (Fig 3). The platelet GPIb recorded 3 hours after the end of the operation was close to the initial values (ie, 97% ± 10.9% and 104.8% ± 17.6% of the baseline values in the NO-treated and control patients, respectively). The difference in platelet GPIb expression between the groups was statistically significant (p = 0.04 by analysis of variance, treatment x time effect).



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  		Fig 3. Platelet glycoprotein IB (GPIb) expression in the control and nitric oxide (NO) groups during cardiopulmonary bypass (CPB). The values are given as the mean plus or minus the standard error of the mean and were normalized to the values recorded before anesthesia. The difference between the two study groups was statistically significant (p = 0.035 by analysis of variance, treatment x time effect).

 
The platelet membrane expression of GPIIb/IIIa remained stable throughout the operation, and no difference could be discerned between the NO and control groups (Fig 4).



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  		Fig 4. Platelet membrane glycoprotein IIb/IIIa (GPIIb/IIIa) expression in the control and nitric oxide (NO) groups during cardiopulmonary bypass (CPB). The values are given as the mean plus or minus the standard error of the mean and were normalized to the values recorded before anesthesia. No statistically significant difference was observed between the two study groups.

 
The platelet aggregation response to adenosine diphosphate was reduced slightly in the blood samples obtained during and 3 hours after the operation, compared with the baseline recordings. However, no difference in adenosine diphosphate–induced platelet aggregation was seen between the NO and control groups (Table 1).


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  		Table 1. Results of Adenosine Diphosphate–Induced Platelet Aggregationa

 
The plasma nitrate concentrations were stable throughout the entire operation, and this was true for both the NO-treated patients and the control patients (Fig 5). The mean plasma nitrate values recorded at the start of the operation were 51.0 ± 10.3 mmol/L and 38.2 ± 7.6 mmol/L in the NO and control groups, respectively. At 30 minutes of extracorporeal circulation, the corresponding values were at 50.25 ± 7.4 mmol/L and 34.9 ± 5.6 mmol/L. At 3 hours after the end of the operation, the mean plasma nitrate levels were 47.8 ± 6.3 mmol/L and 34.4 ± 6.6 mmol/L in the NO and control groups, respectively. The difference in plasma nitrate levels between the two groups of patients was not statistically significant.



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  		Fig 5. Plasma nitrate concentrations in the control and nitric oxide (NO) groups during cardiopulmonary bypass (CPB). The values are given as the mean plus or minus the standard error of the mean. No statistically significant difference was observed between the two study groups.

 
The plasma concentration of hemoglobin increased from 27.3 ± 4.8 mg/L at baseline in the NO group to 368.9 ± 46.0 mg/L at the end of the operation. The corresponding values in the control group were at 28.4 ± 7.9 mg/L at baseline and 463.4 ± 72.2 at the end of the operation (Fig 6). The difference between the groups was not statistically significant.



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  		Fig 6. Plasma hemoglobin concentrations in the control and nitric oxide (NO) groups during cardiopulmonary bypass (CPB). The values are given as the mean plus or minus the standard error of the mean. No statistically significant difference was observed between the two study groups.

 
The whole blood methemoglobin concentration was low in all patients, and did not exceed 1% at any time point studied. The NO2 concentration in the sweep gas, immediately ahead of the oxygenator, was 0.01 to 0.02 ppm. The mean NO concentration at the outlet of the oxygenator was 16.2 ± 1.0 ppm.

No statistically significant difference was noted between the study groups in postoperative blood loss (990 ± 150 mL in the NO group versus 804 ± 114 mL in the control group).

The changes reported did not seem to be dependent on the sex of the patient.


   Comment
Top
 Footnotes
 Abstract
 Introduction
 Material and methods
 Results
 Comment
Acknowledgments
 References
 
In this study, patients who received NO in the oxygenator gas supply during CPB had a slightly lower degree of platelet consumption, whereas no change in the ß-thromboglobulin level, a measure of platelet activation and release, was seen. However, the absence of CPB-induced platelet GPIb upregulation in the NO-treated patients indicates that NO has an effect on the platelet membrane redistribution and trafficking of this glycoprotein [20, 21].

Within a few seconds after the exposure of blood to the artificial material of the extracorporeal circuit, blood proteins such as fibrinogen and von Willebrand factor are adsorbed to the synthetic surfaces [22]. After this protein coating occurs, platelets adhere to the protein layer and become activated [23]. These activated platelets release their granule content and redistribute their membrane glycoproteins, which are held within the open canalicular system [20, 21].

We observed a rapid decline in the platelet count during CPB, a finding that is in accordance with the results obtained by other investigators [7, 8]. This decline in the platelet count can be explained by a combination of hemodilution, clearance of activated platelets from the circulation [24], and adherence of platelets to the artificial surfaces of the extracorporeal circuit. In the patients who received NO, the normalized platelet count was slightly higher during and after CPB, compared with the control patients, but this difference did not reach statistical significance. In previous studies reported by us and by other groups, reduced platelet consumption during in vitro extracorporeal circulation was observed [14, 15]. In addition, during CPB in pigs, when NO is added to the oxygenator sweep gas, a similar effect has been reported [16].

Furthermore, a significant rise in the plasma BTG level was observed in both the NO-treated patients and the control patients in this study. However, no statistically significant difference in plasma BTG levels was observed between the NO and control groups. This is in contrast to our previous in vitro study, in which significantly lower levels of BTG were recorded when the in vitro extracorporeal circuit was supplied with a sweep gas holding NO [15]. These divergent results could be explained by differences in the duration of extracorporeal circulation and the concentrations of NO used, and by changes induced by the surgical trauma. In our previous in vitro study, we used three different concentrations of NO (15, 40, and 75 ppm). In an in vitro model of CPB, Keh and co-workers [16] reported higher platelet counts with the use of 20 ppm of NO. In that study, no variables of platelet activation were reported. In an experimental CPB study performed on 3 pigs, Sly and colleagues [14] reported higher platelet counts in the animals that had 500 ppm of NO added to their sweep gas.

In addition, an increase in platelet membrane expression of GPIb during CPB was noted in our control patients, indicating upregulation of this receptor protein from the platelet open canalicular system. Hence, it is plausible that NO might regulate the platelet membrane density of this receptor protein, playing a crucial role in the process of platelet adhesion. Exogenous NO has been demonstrated to inhibit platelet adhesion under flow conditions [10] and during coronary angioplasty [12].

No increase in the plasma nitrate concentration was noted in our NO-treated patients. This can be explained in part by hemodilution during extracorporeal circulation. In addition, the metabolism of NO during these particular conditions is not yet elucidated. It has been calculated that the distribution volume for nitrate is about 30% of the body weight (ie, a volume more like the extracellular fluid volume than the plasma volume) [19, 25, 26]. This large distribution volume may make it impossible to detect a moderate accumulation of nitrate deriving from the NO administered. Furthermore, little is known about how much of the NO that is given actually is taken up by the oxygenator. In healthy volunteers inhaling 15NO, about 55% of the total amount of NO given was taken up by the lung; in patients with acute lung injury, only 30% was taken up [27].

Our control and treatment groups were disparate in terms of gender and type of operation performed. Regardless, sex did not seem to influence the variables reported.

Nitric oxide might be able to prevent thrombocytopenia and platelet exhaustion, and thereby reduce the frequency of bleeding complications seen in association with extracorporeal circulation. Although we could not prove such an effect during this in vivo study, we suggest that NO, added to the oxygenator sweep gas, protects platelets during extracorporeal circulation.


   Acknowledgments
Top
 Footnotes
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
References
 
This study was supported by grants from AGA AB Medical Research Fund and the Swedish Heart Lung Foundation. We thank Ms Irene Andersson for her expert technical assistance. We also thank Mr Christer Ericson, chief perfusionist, and all the personnel of the Department of Thoracic Surgery at Sahlgrenska University Hospital for their kind support.


   Footnotes
Top
 Footnotes
Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 
This article has been selected for the open discussion forum on the STS Web site: http://www.sts.org/annals


   References
Top
 Footnotes
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 

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The Effect of Nitric Oxide on Platelets When Delivered to the Cardiopulmonary Bypass Circuit
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Y. Suzuki, R. Malekan, C. W. Hanson III, S. Niewiarowski, L. Sun, A. K. Rao, and L. H. Edmunds Jr
PLATELET ANESTHESIA WITH NITRIC OXIDE WITH OR WITHOUT EPTIFIBATIDE DURING CARDIOPULMONARY BYPASS IN BABOONS
J. Thorac. Cardiovasc. Surg., May 1, 1999; 117(5): 987 - 993.
[Abstract] [Full Text] [PDF]

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