| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Ann Thorac Surg 2004;78:1389-1396
© 2004 The Society of Thoracic Surgeons
a Division of Cardiology, Hospital for Sick Children, Toronto, Ontario, Canada
b Department of Cardiac Surgery, Toronto, Ontario, Canada
c Department of Cardiac Intensive Care, Great Ormond Street Hospital, London, United Kingdom
Accepted for publication February 10, 2004.
* Address reprint requests to Dr Redington, Division of Cardiology, The Hospital for Sick Children, 555 University Ave, Toronto, Ontario, Canada M5G 1X8
andrew.redington{at}sickkids.ca
 |
Abstract |
|---|
 Top Abstract IntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
|---|
O2) and delivery (DO2) is impaired after cardiopulmonary bypass (CPB) and is related to systemic inflammatory response syndrome. We sought to assess O2 and DO2 and their relationship with proinflammatory cytokines after CPB with the use of modified ultrafiltration (MUF) in infants.
METHODS: Sixteen infants, aged 1–11.5 months (median, 6.3 months), undergoing hypothermic CPB with MUF were studied during the first 12 hours after arrival in the intensive care unit (ICU). The central temperature was maintained at 36.8–37.1°C using external cooling or warming. O2 was continuously measured using respiratory mass spectrometry. Arterial blood samples for the tumor necrosis factor (TNF), interleukin-6 (IL-6), and interleukin-8 (IL-8) were taken and DO2 was calculated using the Fick principle on arrival at the ICU, and 2, 4, 8, and 12 hours postoperatively. Cytokines were additionally measured after induction of anesthesia and at the end of MUF.
RESULTS: O2 significantly decreased by 18.8% during the study period. DO2 was depressed throughout this period and reached a nadir at 8 hours (357.1 ± 136.2 ml · min–1 · m–2). The decrease in cytokines was accompanied with the decrease in O2 despite varied relationships between the levels of each of the cytokines and O2 measurements.
CONCLUSIONS: Our data indicate an unusual continuous decrease in O2 during the first 12 hours after CPB in infants. Control of body temperature to maintain euthermia in addition to the use of MUF may be beneficial to the balance between O2 and DO2 in the early postoperative period.
|
Introduction |
|---|
|
TopAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
|---|
O2) have been indicated as being related to central body temperature [1] and the systemic inflammatory response [2]. We, as well as others, have assessed these changes during the early hours after CPB in children [3, 4]. We previously demonstrated that the uniformly observed increase in O2 was attributable, in part, to the increase in the central body temperature in children during spontaneously rewarming and fever after CPB [3]. There was an approximate 11% rise in O2 per °C rise in central temperature. The development of fever occurred in 75%. The technique of modified ultrafiltration (MUF) has become widely adopted for use with hemodilutional CPB primarily for the purpose of reducing the accumulated total body water [5, 6]. MUF has subsequently been established to reduce plasma concentration of the inflammatory mediators such as the tumor necrosis factor (TNF), interleukin-6 (IL-6), and interleukin-8 (IL-8) [7, 8]. Furthermore we have demonstrated that MUF leads to improved left ventricular systolic function [9–11] that may further affect the balance between DO2 and O2.
Studies of the effects of cytokines on euthermic O2 after MUF have yet to be performed. The aim of our study was therefore to assess systemic O2 and its relationship with DO2 and cytokine levels in infants under normothermia during the first 12 hours after CPB with the use of MUF.
|
Material and Methods |
|---|
|
TopAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
|---|
|
CPB was performed with moderate-to-deep hypothermia with the lowest nasopharyngeal temperature between 16° and 32°C (median 25°C). The priming solution was a mixture of whole blood and Hartmann's solution in a ratio calculated to achieve a hemoglobin concentration of 8–9 g/dl. Each patient received cold crystalloid cardioplegia (St. Thomas' solution 120 ml/kg) delivered into the aortic root at 40 mm Hg after aortic cross-clamping (ACC). Nonpulsatile flow on CPB was maintained at 150 ml/kg per minute and mean perfusion pressure was adjusted between 40–50 mm Hg using isoflurane to vasodilate and metaraminol to vasoconstrict when required. CPB was maintained for 50–187 minutes (median 86 minutes) and ACC for 19–125 minutes (median 48 minutes) (Table 1). All patients were weaned from CPB after the nasopharygeal temperature reached 35°C and hemodynamic stability was achieved. A pulmonary arterial line was inserted before the termination of CPB. Positive pressure ventilation was recommenced after the discontinuation of CPB.
MUF was performed for 10 minutes within 5–10 minutes of cessation of CPB using the Great Ormond Street Hospital protocol [5] with a pediatric hemofilter (Pediatric Filtral 66; Gambro, Engstrom, Sweden). Flow through the filter was maintained at 200 ml/min by an inlet roller pump and outlet resistance varied to maintain a filtration rate of 100–150 ml/min. The previously optimized left atrial pressure was maintained during filtration by transfusion from the venous reservoir through the filter. Filtration was performed for 10 minutes aiming to achieve a hematocrit of 35%–40%.
The time between termination of CPB and returning to the ICU was less than 2 hours for all patients. Upon return to the ICU patients were mechanically ventilated using volume cycled intermittent positive pressure ventilation (Servo ventilator 900C; Siemens Medical Systems, Solna, Sweden). All received continuous intravenous infusions of vecuronium (1–3 µg · kg–1 · h–1), morphine (20–40 µg · kg–1 · h–1), and midazolam (1–3 µg · kg–1 · h–1) until weaning of mechanical ventilation occurred. The minute volume was adjusted to give an arterial carbon dioxide tension of 4–6 kPa. The FiO2 was less than 60% in all patients.
The central body temperature was maintained at around 37°C using a cooling mattress or warming blanket and overhead radiant heater. Dopamine, dobutamine, and glyceryl trinitrate with diuretics (usually frusemide) were used as clinically indicated. Volume infusions (usually packed red blood cells or 5% albumin) were given to maintain adequate filling pressures with systemic perfusion pressures. The patient was extubated upon clinical judgment and the duration of mechanical ventilation was recorded.
All patients underwent continuous invasive monitoring of systemic and pulmonary arterial and central venous pressures. Heart rate was continuously monitored and the central body temperature (rectal) was monitored with standard temperature probe (Hewlett Packard, Bracknell, UK).
O2 was measured continuously with our previously described method [3] using on-line respiratory mass spectrometry. This is a highly sensitive and accurate method for continuous gas analysis that allows simultaneous measurements of multiple gas fractions within a mixture. An AMIS 2000 quadrupole mass spectrometer (Innovision A/S, Odense, Denmark) was adapted for use in patients ventilated with the Servo 900C ventilator. O2 was measured using the mixed expirate inert gas (argon) dilution method [12]. This requires analysis of inspired and expired gases together with the collection of all expired gas. Before beginning the study the cuff of the endotracheal tube was inflated to prevent leakage. The pressure within the cuff was measured with a manometer to prevent hypoperfusion of the airway mucosa and it was maintained below arterial diastolic pressure. A two-point calibration of the mass spectrometer was performed exposing the distal inlet both to a four-gas calibration mixture (nitrogen, oxygen, carbon dioxide, and argon) and to zero gas (closed inlet). This calibration was repeated at 30-minute intervals throughout the study period to avoid any measurement drift. The calibration of tracer gas flow (argon) was achieved using a designated flow meter (CT Platon, Basingstoke, UK, accuracy ± 1.25%). Ambient humidity, temperature, and atmospheric pressure were recorded from an electronic barometer (BA-888; Oregon Scientific, Portland, OR).
Arterial and mixed venous blood samples were taken from the peripheral arterial and pulmonary arterial catheters. Sampling was avoided if a change in ventilatory or hemodynamic support was assessed within 15 minutes. Blood samples were analyzed for oxygen, carbon dioxide, and lactate levels using the I-STAT Portable Clinical Analyzer (Hewlett-Packard, GmbH Bolingen, Germany; Chiron Diagnostics, Halstead, UK). Cardiac output (CO) was then calculated using the direct Fick method according to the following equation:
 |
The cardiac index (CI) was calculated according to body surface area (BSA):
 |
 |
 |
Plasma, obtained by centrifugation, was placed in aliquots and stored at –70°C for the measurement of IL-6, IL-8, and TNF using commercially available enzyme-linked immunosorbant assay (ELISA) antibody pairs (Cytoset; Biosource International, Camarillo, CA). Preliminary experiments optimized manufacturer's guidelines to achieve a lower detection limit of 3 pg/mL for IL-6, IL-8, and TNF. All samples were analyzed in duplicate by an individual who was blinded to the treatment protocol.
Values of hemodynamics, O2, and central body temperature were obtained and blood samples were taken at the following time: upon admission to the ICU and after 2, 4, 8, and 12 hours during mechanical ventilation. Blood samples for the cytokines were additionally taken after induction of anesthesia and at the end of MUF.
|
O2, temperature, and the levels of circulating cytokines during the study period. p values less than 0.05 were considered significant. |
Results |
|---|
|
TopAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
|---|
Table 2 indicates the mean ± SD values of central temperature, oxygen transport, and arterial lactate and cytokine levels during the study period. Upon arrival to the ICU, arterial blood lactate was less than 2.0 mmol/L in 12 patients, between 2.0–3.0 mmol/L in 2 patients, and 10.4 mmol/L in one patient. This latter patient (patient 11) had a low body weight (2.7 kg), the longest duration of CPB and ACC, the lowest central temperature (34.6°C), the lowest levels of O2 (83.6 ml · min–1 · m–2), CI (1.1 L · min–1 · m–2), DO2 (132.4 ml · min–1 · m–2), and the highest levels of ERO2 (0.63). In the remainder the initial O2 indicated no correlation with the duration of CPB (r = –0.06), ACC (r = –0.16), the depth of hypothermia (r = 0.04), and the central temperature (r = –0.11). The duration of CPB and ACC were negatively correlated with DO2 (r = –0.41 and –0.43, respectively), being weaker with CI (r = –0.25 and –0.21, respectively), and were positively correlated with ERO2 (r = 0.45 and 0.42, respectively). The duration of CPB was positively correlated with the blood lactate levels (r = 0.46, p = 0.04) but not that of ACC (r = 0.06). None of the correlations was significant (p > 0.05 for all).
|
O2 decreased significantly during the study period (p < 0.001) with a faster decrease after 4 hours. There was no significant change in central temperature (p = 0.184). No relationship was determined between the changes in O2 and temperature during the study period (p = 0.910). CI and DO2 decreased insignificantly (p = 0.200 and = 0.351, respectively) with the lowest levels at 8 hours after ICU admission (p = 0.046 and 0.16, respectively, when compared with the initial values). The lowest levels of CI and DO2 at 8 hours negatively correlated with CPB time (r = –0.42, p = 0.04 and –0.51, p = 0.02, respectively) and ACC time (r = –0.35, p > 0.05 and –0.52, p = 0.03, respectively). ERO2 decreased significantly to 0.36 ± 0.1 (p = 0.005). Lactate decreased insignificantly (p = 0.187). The decreases in all the variables over the study period were not correlated with ACC and CPB times (r = –0.01–0.21, p > 0.05 for all).
When individual patients were reviewed, CI and DO2 were more varied relative to O2 at each time point of measurement during the study period, as was ERO2, therefore no consistent correlations were determined between O2 and DO2 or O2 and ERO2 in individual patients (r = –0.60–0.91). The lowest CI and DO2 were variably recorded between arrival up to 12 hours differently in individuals. CI was less than 2.0 L · min–1 · m–2 at least once in 11 patients. Dopamine was given in 9 patients among whom 8 patients indicated CI lower than 2 L · min–1 · m–2 at least once. Dobutamine was given in 4 patients and glyceryl trinitrate was given to all patients. Blood lactate returned to below 2 mmol/L in all of the patients by the end of the study period including the one (patient 11) with an initial lactate level of 10.4 mmol/L who was extubated 24 hours after admission to the ICU.
The concentrations of all the cytokines, TNF, IL-8, and IL-6, increased after CPB and peaked at ICU admission (Fig 2). TNF concentrations were low preoperatively and remained so throughout the study period without substantial differences regarding the sampling time. IL-8 concentrations, although also not being statistically different, increased noticeably after CPB and peaked at ICU admission, which was followed by a significant decrease (p = 0.009). The mean IL-6 concentrations increased insignificantly at the end of CPB (p = 0.051) peaking upon admission to the ICU (p = 0.002 as compared with the preoperative baseline concentrations) and then decreasing slightly (p = 0.170). In individual patients the peak time of IL-6 concentrations indicated wide variations, whereas that of IL-8 and TNF indicated a more consistent profile of peaking upon ICU admission. Large individual variations were also determined regarding the concentrations of the three cytokines. General linear multiple regression analysis indicates different relationships between the levels of O2 and the levels of each of the cytokines during the study period being not significantly related to TNF (p = 0.138), positively related to IL-8 (p = 0.021), and negatively related to IL-6 (p = 0.003). The patient (patient 11) who exhibited the longest CPB and ACC time associated with the lowest levels of CI, DO2, and O2 indicated the highest levels of the three cytokines at all the sampling times with TNF being 281 pg/ml, IL-8 being 533 pg/ml, and IL-6 being 788 pg/ml upon ICU admission. In the rest of the patients no correlations were indicated between the durations of ACC and CPB with any of the cytokine levels (r < 0.30 and p > 0.05 for all patients).
|
|
Comment |
|---|
|
TopAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
|---|
O2 and DO2 in euthermic infants during the early hours after hypothermic CPB surgery succeeding the use of the MUF. In contrast to all previous analysis [1–4, 13, 14] our data demonstrated that under these circumstances the initially high O2 continuously decreased during this early postoperative period and was associated with a decrease in circulating cytokine levels. CI and DO2 were depressed with the lowest levels indicated at 8 hours after admission to the ICU.
In our previous study of O2 in children during spontaneously rewarming during the first 4 hours after CPB [3], there was an 11.3% ± 8.0% increase in O2 per 1°C rise in central temperature. The postoperative increase in central body temperature may be attributed to two factors: normal homeostatic rewarming and fever induced by the inflammatory response after hypothermic CPB. Therefore the external warming and cooling for the maintenance of central temperature as used in our infants may have avoided the "metabolic cost" of temperature rise, which leads to an increase in O2.
Although not previously described in children the provision of external heat supply has been reported to reduce the O2 in adults during the rewarming period [15, 16]. External heat supply is a common clinical practice with regard to the care of infants during rewarming after hypothermia CPB surgery and our data suggests that it may also exhibit similar effects to reduce O2 in children. Conversely external cooling to prevent fever may play a similar role in the attenuation of the associated rise in O2. Maintenance of euthermia is part of the routine clinical management of patients after cardiac surgery in some centers. Our data may provide some support for its potential benefits in terms of O2. However other factors than just temperature, such as the application of MUF with its possible effect on cytokine levels, may also contribute in part to the decreased O2 in the current study.
MUF, which is commonly used for reducing the accumulated tissue water with hypothermic hemodilutional CPB [5, 6], has also been revealed to filter at least some cytokines including TNF, IL-6, and IL-8 [7, 8, 11]. The increased levels of cytokines are now believed to be the key factors during the systemic inflammatory response induced by hypothermic CPB [17–19]. Oudemans-van Straaten and associates demonstrated that higher circulating levels of cytokines including TNF and IL-6 were associated with a higher O2 after CPB surgery and concluded that the systemic inflammatory response may explain 50% of the increase of O2 [2]. It has been reported that the increased levels of cytokines are related to the duration of ACC and CPB [17, 18]. The longest duration of ACC and CPB was related to the highest levels of cytokines in one of the patients, but there was no correlation between the duration of ACC and CPB with cytokine levels in the remaining patients. Nonetheless this relationship may have been altered by the generally attenuated levels of cytokines after the use of MUF in our patients. The TNF levels in the current study were low throughout the study period including preoperatively. This is consistent with some pediatric studies [17] but different from others that describe a substantial increase after CPB [20]. Compared with other studies in children undergoing CPB without the use of MUF, postoperative IL-8 levels in our infants were considerably lower [17, 21]. Postoperative IL-6 levels were much more variable being similar to some [17, 21] and considerably lower than some others [19, 22]. When compared with a study of children regarding the use of MUF [23] TNF was considerably lower and IL-6 higher in our infants. The comparison of data in other reports is difficult however. It has been well documented that the cytokine response to CPB in children is characterized by large variations in the pattern of release and plasma concentrations [21, 23] in contrast to adults [24]. Indeed there was large interindividual variability between patients in our study despite a very rigid management protocol. Furthermore different assay sensitivities for the measurements of cytokines and different degrees of hemodilution may contribute to the varied results among studies [22]. Nonetheless the cytokine levels subsequently decreased further continuously after admission to the ICU, which accompanied the decrease in O2. The role of cytokines in the modulation of O2 is further supported by Oudemans-van Straaten's other study in which a nonsignificant increase in O2 during the early hours after CPB was attributed to the prevention of the TNF-related inflammatory response with the prophylactic use of dexamethasone [25]. This study and our current study demonstrate a lack of increase in O2 in the first hours after CPB. Our data indicated different relationships between the O2 values and the levels of the different cytokines during the study period, not being notably related with TNF, positively related with IL-8, and negatively related with IL-6. The overall factors including the attenuated levels of cytokines with wide interindividual variations together with the absence of the increase in O2 may help to explain the varied relationships between cytokine levels and O2 in our patients.
DO2, as well as CI, in our patients was depressed during the early hours after CPB reaching a nadir at 8 hours after ICU admission. This typical profile of cardiac function after CPB surgery has been generally described in children [26, 27] and in adults [28]. This sequence is related to ischemia-reperfusion injury and the secondary effects of the systemic inflammatory response [17, 28]. Although MUF has been reported to improve left ventricular systolic function [9, 10] the overall CI was low in our patients; values were similar to those in previously reported studies for neonates and infants after cardiac surgery [17, 26, 27, 29] Most infants exhibit more complex congenital heart disease requiring earlier surgical correction with longer duration of CPB and ACC time. Indeed the longer duration of CPB and ACC in our patients illustrated a tendency toward association with lower initial CI and DO2 levels and the lowest levels at 8 hours resulting in a poorer balance between O2 and DO2 as indicated by the higher lactate levels. Thus this continuous decrease in O2 in our patients demonstrates a beneficial effect toward improving the balance of oxygen transport in children experiencing more profound depression of DO2.
It is a necessity to mention that there were considerable variations of DO2 relative to O2 in individual patients from time to time over the study period. The clinicians caring for these patients may have been likely to respond to the hemodynamic changes by unnecessary augmentation to obtain "normal" hemodynamic values with no regard for O2. The potential complications of the unnecessary augmentation of CI and DO2 under these circumstances are well understood [21, 30] but guidelines for "appropriate" hemodynamic values remain lacking and may only be obtained with improved insights of O2. For example an uneventful recovery of patient 11 occurred despite the lowest CI and DO2 throughout the study period allowing for a stable, as well as the lowest, O2. Treatment aiming to correct hemodynamic imbalance should be guided by information regarding the balance between O2 and DO2.
One of the major limitations of our study was the lack of a control group. MUF with postoperative euthermia has become a standard of care in our institution and it was not impossible to justify a control group without MUF with or without the development of postoperative pyrexia. Another limitation was that neonates were not studied. This was because of methodological issues concerning the use of cuffed endotracheal tubes in small infants. Nonetheless we cannot exclude different responses of oxygen transport to CPB because of the possibly different profiles of hormonal and inflammatory responses in younger patients [31, 32]
The hitherto unreported continuous decrease in O2 during the first 12 hours after CPB with the use of MUF in this study suggests improved balance between oxygen consumption (O2) and delivery (DO2) in these euthermic infants with depressed cardiac function. Thus despite a falling CI and DO2 the fall in O2 obviated the considerable imbalance in oxygen transport. Indeed the more direct manipulation of O2 under circumstances of reduced CI and DO2 warrants further investigation into the management of postoperative low cardiac output syndrome.
|
Acknowledgments |
|---|
|
TopAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
|---|
|
References |
|---|
|
TopAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
|---|
This article has been cited by other articles:
|
|
 |
|
  J. Li, G. Zhang, B. W. McCrindle, H. Holtby, T. Humpl, S. Cai, C. A. Caldarone, A. N. Redington, and G. S. Van Arsdell Profiles of hemodynamics and oxygen transport derived by using continuous measured oxygen consumption after the Norwood procedure J. Thorac. Cardiovasc. Surg., February 1, 2007; 133(2): 441 - 448. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Li, G. Zhang, H. Holtby, T. Humpl, C. A. Caldarone, G. S. Van Arsdell, and A. N. Redington Adverse Effects of Dopamine on Systemic Hemodynamic Status and Oxygen Transport in Neonates After the Norwood Procedure J. Am. Coll. Cardiol., November 7, 2006; 48(9): 1859 - 1864. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. M Medlin and J. J Sistino Cerebral oxygen saturation changes during modified ultrafiltration Perfusion, November 1, 2006; 21(6): 325 - 328. [Abstract] [PDF]
|
|
|
|
|
|
J. Li, G. Zhang, H. M. Holtby, B. W. McCrindle, S. Cai, T. Humpl, C. A. Caldarone, W. G. Williams, A. N. Redington, and G. S. Van Arsdell Inclusion of oxygen consumption improves the accuracy of arterial and venous oxygen saturation interpretation after the Norwood procedure J. Thorac. Cardiovasc. Surg., May 1, 2006; 131(5): 1099 - 1107. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| ANN THORAC SURG | ASIAN CARDIOVASC THORAC ANN | EUR J CARDIOTHORAC SURG |
| J THORAC CARDIOVASC SURG | ICVTS | ALL CTSNet JOURNALS |
