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Clinical Sciences
Intrathecal Morphine Plus General Anesthesia in Cardiac Surgery: Effects on Pulmonary Function, Postoperative Analgesia, and Plasma Morphine Concentration
Luciana Moraes dos SantosI, Verônica Cavani Jorge SantosII, Silvia Regina Cavani Jorge SantosII, Luiz Marcelo Sá MalbouissonII,
Corresponding author
lumoraesrj@yahoo.com.br

Phone: 55 16 3602.2211
, Maria José Carvalho CarmonaI
I Department of Anesthesia, Heart Institute, Faculdade de Medicina da Universidade de São Paulo - São Paulo/SP, Brazil
II Department of Clinical Pharmacology, Pharmaceutical Sciences School, Universidade de Sao Paulo - São Paulo/SP, Brazil
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="cesec10" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle70">INTRODUCTION</span><p id="para10" class="elsevierStylePara elsevierViewall">Lung dysfunction after cardiac surgery is the most frequently reported cause of postoperative morbidity&#46;<a class="elsevierStyleCrossRef" href="#bib1">1</a>&#44;<a class="elsevierStyleCrossRef" href="#bib2">2</a> In fact&#44; postoperative atelectasis occurs more frequently in patients undergoing cardiac surgery with cardiopulmonary bypass &#40;CPB&#41; than in any other type of surgery<a class="elsevierStyleCrossRef" href="#bib3">3</a> In patients undergoing cardiac surgery&#44; death caused by respiratory complications has been reported as being more frequent than that due to cardiac causes&#46;<a class="elsevierStyleCrossRef" href="#bib4">4</a> Adequate perioperative analgesia enables full expansion of the chest&#44; thereby contributing to reduce lung collapse in spontaneously breathing patients&#46; This therapeutic intervention may reduce morbidity&#44; hospital costs&#44; and length of stay&#44; thus improving patient quality of life and reducing the incidence of chronic pain&#46;<a class="elsevierStyleCrossRef" href="#bib5">5</a></p><p id="para20" class="elsevierStylePara elsevierViewall">The impact of postoperative regional analgesia on major outcomes in non-cardiac surgery has been studied&#46;<a class="elsevierStyleCrossRefs" href="#bib6">6&#8211;8</a> Small doses of opioids administered to the central nervous system provide adequate analgesia&#44; reducing the risks of intravenous analgesic administration&#44; such as respiratory depression&#44; pruritus&#44; nausea&#44; and vomiting&#46; However&#44; in the cardiac surgical population&#44; regional anesthesia techniques are not routinely applied due to the scarcity of supporting studies and administration risks associated with preoperative systemic anticoagulation<a class="elsevierStyleCrossRef" href="#bib9">9</a> Low doses of intrathecal morphine used to control postoperative pain has been shown to promote prolonged analgesia&#44;<a class="elsevierStyleCrossRef" href="#bib5">5</a> and has been associated with a lower risk of hematoma formation compared to the epidural technique&#46;<a class="elsevierStyleCrossRef" href="#bib10">10</a> Intrathecal morphine has been studied for several years in patients undergoing cardiac surgery&#44; but these studies were primarily directed towards evaluation of pain control and hemodynamic stability&#44; and did not consider its possible impact of intrathecal morphine on respiratory function recovery&#46;<a class="elsevierStyleCrossRef" href="#bib11">11</a></p><p id="para30" class="elsevierStylePara elsevierViewall">The objective of this study was to evaluate the effects of intrathecal morphine on pulmonary function&#44; postoperative analgesia&#44; and morphine plasma concentrations in patients undergoing coronary artery bypass surgery &#40;CABG&#41; with cardiopulmonary bypass &#40;CPB&#41; in comparison to standard intravenous analgesia&#46;</p></span><span id="cesec20" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle80">MATERIALS AND METHODS</span><p id="para40" class="elsevierStylePara elsevierViewall">After approval of the hospital ethics committee and collection of free informed consent&#44; forty-two patients undergoing CABG with CPB and ranging in age from 18 to 80 years were included&#46; Exclusion criteria were an ejection fraction below 40&#37;&#44; contraindications to neuraxial blockage&#44; coagulopathy&#44; use of low-weight heparin&#44; warfarin&#44; intrathecal morphine&#44; or a platelet aggregation inhibitor other than aspirin&#44; systemic or local infection&#44; combined procedures&#44; and patients with a specific contraindication to the medication employed in this study&#46; Preoperative aspirin use was not an exclusion criterion&#46; Preoperative surgical risk was evaluated using Higgins Surgical Risk Scale for cardiac surgery&#44; and patients were considered&#58; &#40;1&#41; minimum risk&#44; &#40;2&#41; low risk&#44; &#40;3&#41; moderate&#44; &#40;4&#41; high&#44; &#40;5&#41; extreme risk<a class="elsevierStyleCrossRef" href="#bib12">12</a>&#46; The patients were randomly assigned to receive general anesthesia with prior administration of intrathecal morphine at a dosage of 400 &#956;g &#40;morphine group n&#61;20&#41; or general anesthesia alone &#40;control group n&#61;22&#41; according to a simple computer-generated list&#46;</p><span id="cesec30" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle90">Anesthesia and surgical procedures</span><p id="para50" class="elsevierStylePara elsevierViewall">On the day of the operation&#44; the patients received 1 to 2 mg kg <span class="elsevierStyleSup">&#8722;1</span> of midazolam orally 30 minutes before surgery&#44; up to a maximal dose of 15 mg&#46; Patients were monitored by continuous ECG and ST-analysis&#44; pulse oximetry&#44; and an invasive arterial line inserted in the right radial artery&#46; In the morphine group&#44; a 400-&#956;g intrathecal injection of morphine was administered using a 27-gauge spinal needle in the L3-L4 space prior to induction of general anesthesia&#46; If intrathecal puncture was not successful after two attempts&#44; the patient was excluded from the study&#46;</p><p id="para60" class="elsevierStylePara elsevierViewall">After pre-oxygenation&#44; general anesthesia was induced using 0&#46;3 mg&#47;kg of hypnomidate&#44; 0&#46;1 mg kg<span class="elsevierStyleSup">&#8722;1</span> of pancuroniun bromide&#44; and 0&#46;5 &#956;g kg<span class="elsevierStyleSup">&#8722;1</span> of sufentanil first as a bolus&#44; followed by a continuous infusion at 0&#46;5 &#956;g kg<span class="elsevierStyleSup">&#8722;1</span> h<span class="elsevierStyleSup">&#8722;1</span>&#46; Mechanical ventilation was initiated using a C&#237;cero ventilator &#40;Dr&#228;ger&#174;&#44; Germany&#41; with a tidal volume of 8 ml kg<span class="elsevierStyleSup">&#8722;1</span>&#44; respiratory frequency of 12 ipm&#44; oxygen inspired fraction of 0&#46;6&#37;&#44; and 5 cm of H<span class="elsevierStyleInf">2</span>O PEEP&#46; A nasoesophageal thermometer&#44; bladder catheter&#44; and central venous catheter were inserted after anesthesia induction&#46; When judged necessary by the attending anesthesiologist&#44; a pulmonary artery catheter was placed in the right internal jugular vein&#46; Immediately after intubation and after CPB weaning&#44; a lung expansion maneuver using an airway pressure of 30 cmH<span class="elsevierStyleInf">2</span>O for 20 seconds was performed to revert any intraoperative lung collapse&#46; During CPB&#44; hypnosis was maintained with a propofol infusion aimed at maintaining a calculated plasma propofol concentration of 2&#46;5 ug ml<span class="elsevierStyleSup">&#8722;1</span> according to the Marsh model<a class="elsevierStyleCrossRef" href="#bib13">13</a>&#46; All patients received 1 g of methylprednisolone intravenously before initiation of CPB according to the institutional protocol&#46; Sufentanil infusion was terminated at the moment of skin suture&#46;</p><p id="para70" class="elsevierStylePara elsevierViewall">After arrival in the intensive care unit &#40;ICU&#41;&#44; a patient-controlled analgesia pump &#40;PCA&#41; programmed for a 1 mg bolus of morphine with an administration interval locked at 5 minutes and free demand was installed&#46; Dipyrone &#40;30 mg kg<span class="elsevierStyleSup">&#8722;1</span>&#41; was administered if patients presented persistent pain despite the use of PCA&#46; Tracheal extubation was performed when patients were fully awake and responsive to verbal commands&#44; as well as when the peripheral oximetry was greater than 94&#37;&#44; spontaneous respiratory frequency was greater than 10&#44; temperature was greater than 36&#176; C&#44; and the patient was hemodynamically stable such that they were bleeding less than 100 ml&#47;h&#46;</p></span><span id="cesec40" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle100">Ventilatory and pain score evaluation</span><p id="para80" class="elsevierStylePara elsevierViewall">Spirometry using an Easy One&#174; portable spirometer &#40;Niche Medical&#44; West Leederville&#44; Australia&#41; was also performed preoperatively in the first and second postoperative days &#40;POD&#41; to measure forced vital capacity &#40;FVC&#41;&#44; forced expiratory volume in the first second &#40;FEV1&#41;&#44; and thus the FEV1&#47;FVC ratio&#46; Arterial blood samples were collected during the preoperative period&#44; immediately before surgery&#44; after anesthesia induction&#44; at the end of surgery&#44; and in the first and second postoperative days to evaluate the PaO<span class="elsevierStyleInf">2</span>&#47;FiO<span class="elsevierStyleInf">2</span> ratio&#46; Pain was evaluated using a visual numeric scale from zero to ten at rest&#44; at the time of profound inspiration&#44; and after cough at 3&#44; 6&#44; 12&#44; 18&#44; 24&#44; and 36 hours postoperatively&#46; Morphine cumulative consumption and solicitation was also evaluated at the same times listed above&#46; All postoperative pain&#44; respiratory function&#44; and morphine utilization measurements were obtained by individuals who were not involved in patient randomization and anesthesia administration&#46;</p><p id="para90" class="elsevierStylePara elsevierViewall">Blood samples assessed for plasma morphine concentrations were collected intraoperatively&#44; immediately after stopping sufentanil infusion&#44; after 5&#44; 15&#44; 30&#44; and 60 minutes&#44; and after 3&#44; 6&#44; 12&#44; 18&#44; 24&#44; and 36 hours in the ICU&#46; The blood samples were centrifuged at 10&#46;000 rpm for 10 minutes&#44; and the supernatant was frozen at &#8722; 70 &#186;C for later analysis&#46; Plasma morphine concentrations were measured using a mass spectrophotometer&#46;</p></span><span id="cesec50" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle110">Sample size and statistical analysis</span><p id="para100" class="elsevierStylePara elsevierViewall">A sample size of at least 36 patients was deemed necessary to detect a statistically significant decrease &#40;p &#60; 0&#46;05&#41; in cumulative morphine consumption of 20&#37; between the morphine and control group&#44; assuming a standard deviation of 10 mg in a single-tail paired Student&#8217;s t-test using G Power 3 software &#40;Heinrich-Heine-Universit&#228;t D&#252;sseldorf&#44; D&#252;sseldorf&#44; Germany&#41;&#46;</p><p id="para110" class="elsevierStylePara elsevierViewall">Statistical analyses were performed using SPSS 16&#46;0 software &#40;SPSS Inc&#46;&#44; Chicago&#44; Ilinois&#41;&#46; The normal distribution of the collected data was confirmed by means of the Kolmogorov-Smirnov test&#46; Demographic and surgical data were compared between groups using the unpaired Student&#8217;s t-test&#46; Spirometric variables were compared over time between the groups using repeated measures analysis of variance&#44; followed by the Student-Neumann-Keuls post hoc test when necessary&#46; Pain scores and cumulative morphine consumption were analyzed by means of the Friedman test&#44; followed by the Mann-Whitney test when necessary&#46; All data are presented as mean values &#177; standard deviation&#44; error means&#44; or as otherwise described&#46; The significance level was fixed at 5&#37;&#46;</p></span></span><span id="cesec60" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle120">RESULTS</span><p id="para120" class="elsevierStylePara elsevierViewall">Patient characteristics and general variables are presented in Table <a class="elsevierStyleCrossRef" href="#tbl1">1</a>&#46; There were no differences between groups with regard to the variables represented in Table <a class="elsevierStyleCrossRef" href="#tbl1">1</a>&#46; Mean surgery duration and CPB length were similar in both groups &#40;392 &#177; 70 vs&#46; 379 &#177; 91 minutes&#41; and &#40;98 &#177; 26 vs&#46; 95 &#177; 38 minutes&#41; &#40;p&#61;0&#46;606 and p&#61;0&#46;780&#44; respectively&#41;&#46; Minimal temperature values were 31&#46;3 &#177; 2&#46;7&#176;C in the control group and 30&#46;7 &#177; 2&#46;7&#176;C in the morphine group &#40;p&#61;0&#46;456&#41;&#46; All patients achieved hemodynamic stability in the immediate postoperative period&#44; permitting weaning off of the vasoactive drugs within the first 24 hours&#46; The total dose of sufentanil employed was 257&#46;77 &#956;g &#177; 81&#46;41 in the control group and 200&#46;87 &#956;g &#177; 55&#46;11 in the morphine group &#40;p&#61; 0&#46;012&#41;&#44; and was related to the duration of surgery&#46; Intrathecal morphine did not shorten the postoperative time to extubation between groups &#40;396 &#177; 234 min in the control group and 349 min &#177; 175 in the morphine group&#44; p&#61;0&#46;466&#41;&#46; None of the patients in our cohort developed respiratory failure after extubation or needed postoperative non-invasive ventilation&#46; All intrathecal punctures were successful at the first or second attempt&#46; No cases of spinal hematoma or treatable pruritus were observed&#46; All patients were discharged from the ICU without postoperative complications&#46;</p><elsevierMultimedia ident="tbl1"></elsevierMultimedia><span id="cesec70" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle130">Gas exchange and Spirometric Analysis</span><p id="para130" class="elsevierStylePara elsevierViewall">Both group presented a significant decrease in FVC and FEV<span class="elsevierStyleInf">1</span> during the first and second postoperative days&#44; with no significant difference between the groups &#40;p&#61;0&#46;068 and 0&#46;085&#44; respectively&#41;&#46; The FEV1&#47;FVC ratio did not differ between groups &#40;p&#61;0&#46;68&#41;&#44; as presented in Table <a class="elsevierStyleCrossRef" href="#tbl2">2</a>&#46; In ratio did not differ between groups addition&#44; the PaO<span class="elsevierStyleInf">2</span>&#47;FiO<span class="elsevierStyleInf">2</span> at any time point &#40;p &#62;0&#46;05&#41;&#44; as presented in Figure <a class="elsevierStyleCrossRef" href="#fig1">1</a>&#46;</p><elsevierMultimedia ident="tbl2"></elsevierMultimedia><elsevierMultimedia ident="fig1"></elsevierMultimedia></span><span id="cesec80" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle140">Pain scores&#44; morphine consumption&#44; and plasma concentrations</span><p id="para140" class="elsevierStylePara elsevierViewall">The intensity of pain at rest and with cough was significantly lower in the morphine group at 12&#44; 18&#44; 24&#44; and 36 hours postoperatively when compared to the control group &#40;p &#60;0&#46;05&#41;&#44; as shown in panels A and C of Figure <a class="elsevierStyleCrossRef" href="#fig2">2</a>&#46; With profound inspiration&#44; patients in the morphine group reported pain levels that were significantly less intense at 12&#44; 18&#44; and 24 hours after surgery &#40;panel B of Figure <a class="elsevierStyleCrossRef" href="#fig2">2</a>&#41;&#46; The venous morphine solicitation count was lower in the morphine group at 18 &#40;control group&#61; 108&#46;3 &#177; 213&#46;8 and morphine group&#61; 20&#46;2 &#177; 30&#46;3&#41; and 24 hours &#40;control group&#61; 144&#46;4 &#177; 251&#46;2 and morphine group&#61; 32&#46;4 &#177; 38&#46;05&#41; &#40;p&#60;0&#46;05&#41;&#46; Cumulative morphine consumption was also reduced in the morphine group at 18 &#40;control group&#61; 20&#46;14 &#177; 17&#46;73 mg and morphine group&#61;14&#46;10 &#177; 26&#46;15 mg&#41;&#44; 24 &#40;control group&#61; 27&#46;82 &#177; 22&#46;77 mg and morphine group&#61; 13&#46;55 &#177; 10&#46;49 mg&#41;&#44; and 36 hours &#40;control group &#61; 38&#46;50 &#177; 26&#46;70 and morphine group&#61; 24&#46;30 &#177; 14&#46;59&#41; postoperatively &#40;Figure <a class="elsevierStyleCrossRef" href="#fig3">3</a>&#41;&#44; as well as upon extubation &#40;control group&#61; 3&#46;32 &#177; 8&#46;17 mg and morphine group&#61; 0&#46;15 &#177; 0&#46;49 mg&#41; &#40;p&#60;0&#46;05&#41;&#46; Plasma morphine levels were zero at the end of surgery in both groups&#46; However&#44; plasma levels were significantly reduced in the morphine group during the postoperative period 24 hours after the operation &#40;control group&#61; 15&#46;87 &#177; 18&#46;05 ng mL<span class="elsevierStyleSup">&#8722;1</span> and morphine group 4&#46;08 &#177; 5&#46;28 ng mL<span class="elsevierStyleSup">&#8722;1</span>&#44; p&#61;0&#46;029&#41;&#44; as presented in Figure <a class="elsevierStyleCrossRef" href="#fig4">4</a>&#46; Nine patients in the control group and five patients in the morphine group requested rescue analgesia with dipyrone &#40;p&#61; 0&#46;460&#41;&#46;</p><elsevierMultimedia ident="fig2"></elsevierMultimedia><elsevierMultimedia ident="fig3"></elsevierMultimedia><elsevierMultimedia ident="fig4"></elsevierMultimedia></span></span><span id="cesec90" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle150">DISCUSSION</span><p id="para150" class="elsevierStylePara elsevierViewall">In the present study&#44; intrathecal morphine administration in patients undergoing coronary artery bypass graft reduced pain scores&#44; postoperative morphine solicitation&#44; and morphine consumption and its plasma concentration&#46; However&#44; despite better analgesic control&#44; no significant improvements in spirometry or gas exchange were observed&#46;</p><p id="para160" class="elsevierStylePara elsevierViewall">Respiratory system dysfunction is the most prevalent organic complication after cardiac surgery&#44; even in the absence of preoperative pulmonary disease<a class="elsevierStyleCrossRef" href="#bib1">1</a>&#46; Perioperative atelectasis leads to a pulmonary ventilation&#47;perfusion mismatch that likely serves as a major cause of shunt and hypoxemia after cardiopulmonary bypass&#46;<a class="elsevierStyleCrossRef" href="#bib14">14</a> The impact of postoperative analgesia techniques on pulmonary function outcome has been well studied in non-cardiac surgery&#44; but few studies to date have examined this matter in cardiac surgery&#46;<a class="elsevierStyleCrossRef" href="#bib8">8</a> A study that enrolled 113 patients submitted for different types of cardiac surgery observed that thoracic epidural analgesia &#40;TEA&#41; combined with general anesthesia followed by patient-controlled thoracic epidural analgesia offered no major advantages with respect to lung function&#44; length of hospital stay&#44; quality of recovery&#44; or morbidity when compared to general anesthesia alone&#44; with both groups followed by patient-controlled analgesia with intravenous morphine&#46;<a class="elsevierStyleCrossRef" href="#bib15">15</a> In contrast&#44; a meta-analysis including 15 trials enrolling 1&#46;178 patients suggested that TEA significantly reduced the risk of pulmonary complications &#40;OR 0&#46;41&#41;&#44; time to tracheal extubation by 4&#46;5 hours&#44; and analog pain scores at rest and with activity&#46;<a class="elsevierStyleCrossRef" href="#bib9">9</a></p><p id="para170" class="elsevierStylePara elsevierViewall">In the present study&#44; intrathecal instead of epidural morphine was used because there is no evidence for analgesia superiority between them&#46; However&#44; the risk of spinal hematoma is lower with the intrathecal technique&#44;<a class="elsevierStyleCrossRef" href="#bib16">16</a> especially with the required anticoagulation prior to cardiac surgery&#46;</p><p id="para180" class="elsevierStylePara elsevierViewall">The last two meta-analyses used to evaluate the use of intrathecal morphine in cardiac surgery did not reveal a correlation between the efficacy of pain control and better respiratory outcome&#44;<a class="elsevierStyleCrossRef" href="#bib3">3</a>&#44;<a class="elsevierStyleCrossRef" href="#bib11">11</a> likely because these studies did not employ lung function as an end-point<a class="elsevierStyleCrossRef" href="#bib11">11</a>&#46; Some of these studies described no improvement of pain control<a class="elsevierStyleCrossRef" href="#bib10">10</a> or modest reduction of pain scores&#44;<a class="elsevierStyleCrossRef" href="#bib11">11</a> with higher doses correlating with better postoperative analgesia<a class="elsevierStyleCrossRef" href="#bib17">17</a> as well as longer time to extubation&#46;<a class="elsevierStyleCrossRef" href="#bib18">18</a> In line with the beginning of the fast-track era and its goal to decrease the intubation time after surgery&#44; changes in anesthesia techniques and a reduction in the dose of intrathecal morphine were previously associated with a decreased time to extubation&#44;<a class="elsevierStyleCrossRef" href="#bib20">20</a> with some cases of prolonged respiratory depression&#46;<a class="elsevierStyleCrossRef" href="#bib21">21</a> A previous study compared intrathecal morphine doses of 250 and 500 &#956;g and placebo&#44; and showed the superiority of intrathecal analgesia&#44; without alterations in gas exchange<a class="elsevierStyleCrossRef" href="#bib19">19</a> or an increase in time to extubation&#46;<a class="elsevierStyleCrossRef" href="#bib22">22</a> In the present study&#44; the selected dose of 400 &#956;g of morphine had no effect on time to tracheal extubation in the postoperative period&#46; According to our results&#44; use of low doses of intrathecal morphine can decrease the intensity of postoperative pain at different times&#44; such as at rest&#44; upon profound inspiration&#44; and upon cough&#46; This suggests that not only does intrathecal morphine provide better analgesia at rest&#44; but also during activities that support walking&#44; respiratory maneuvers&#44; and the use of incentive spirometry&#46; This is important to ensure the quality of patient recovery&#44; since it has been demonstrated that respiratory physiotherapy may reduce rates of pulmonary complications&#46;<a class="elsevierStyleCrossRefs" href="#bib23">23&#8211;25</a></p><p id="para190" class="elsevierStylePara elsevierViewall">Improved analgesia may allow for a decrease in the solicitation and consumption of postoperative analgesics&#44; resulting in lower plasma analgesic levels&#44; as observed in this study&#46; A previous cardiac surgery study that also used intrathecal morphine revealed a venous consumption of 13&#46;5 mg at a dose of 250 &#956;g&#44; and a consumption of 11&#46;7 mg of morphine with an intrathecal dose of 500 &#956;g compared to 21&#46;7 mg in the placebo group 24 hours after the operation&#46;<a class="elsevierStyleCrossRef" href="#bib22">22</a> In a meta-analysis&#44; 668 patients undergoing cardiac surgery were reported to consume 11 mg of intravenous morphine in intrathecal group &#46;<a class="elsevierStyleCrossRef" href="#bib9">9</a></p><p id="para200" class="elsevierStylePara elsevierViewall">The importance of studying the plasma concentration of morphine as a marker for progress in the of treatment of pain was considered by Bonica in 1985&#44; but only a few studies have investigated this idea<a class="elsevierStyleCrossRef" href="#bib26">26</a> Only one study has been published regarding plasma morphine concentrations during patient control analgesia techniques&#44;<a class="elsevierStyleCrossRef" href="#bib27">27</a> and no studies reported intrathecal morphine use in the postoperative period or its correlation with pain scores&#46; In patients undergoing hysterectomy with postoperative PCA&#44; an increase in plasma morphine levels resulted in clinical effects 6 to 12 hours after surgery&#46; This lag could be explained by the delay in morphine passing through the hematoencephalic barrier&#46; After this period&#44; a significant reduction in morphine consumption and pain scores was observed&#44; and this can be explained by maintenance of a steady-state level of morphine sufficient to maintain an effective level of analgesia&#46;<a class="elsevierStyleCrossRef" href="#bib27">27</a> Mutations in the opioid &#956; receptor were described to support the interindividual variability theory in the population and its possible influences on the use of morphine&#46;<a class="elsevierStyleCrossRefs" href="#bib28">28&#8211;30</a></p><p id="para210" class="elsevierStylePara elsevierViewall">Although the number of patients in our study was insufficient to fully evaluate the adverse effects of intrathecal morphine&#44; no cases of spinal hematoma or treatable pruritus were observed in the present study&#46; Previous studies utilizing doses between 5&#8211;24 &#956;g kg<span class="elsevierStyleSup">&#8722;1</span> for cardiac surgery described a 30&#37; incidence of pruritus&#44;<a class="elsevierStyleCrossRef" href="#bib21">21</a> which is the most common symptom observed after morphine treatment&#46; Fortunately&#44; this common side effect becomes severe in only 1&#37; of cases&#46;<a class="elsevierStyleCrossRef" href="#bib31">31</a> The absence of an intrathecal puncture in the control group may have limited our ability to observe adverse effects&#46;</p><p id="para220" class="elsevierStylePara elsevierViewall">Despite the risk of spinal hematoma&#44; the use of intrathecal analgesia in cardiac surgery<a class="elsevierStyleCrossRef" href="#bib32">32</a> has increased&#46; This increase may be explained by the demand for better analgesia with chest tubes&#44; sternotomy&#44; deambulation&#44; and physiotherapy maneuvers in the absence of a trained pain management team and patient-control pumps&#46; Thus&#44; our study has direct clinical applications&#46; Future studies are being conducted to study the effects of pain control on quality of life&#44; satisfaction&#44; and postoperative recovery&#44; since no additional benefits of intrathecal morphine beyond pain control have been shown until now&#46; None of these quality of life or recovery variables have been correlated with better pain scores&#44; but a modest reduction in satisfaction was shown in the presence of adverse effects&#46;<a class="elsevierStyleCrossRef" href="#bib33">33</a> Considering the risks of nerve blockade and required anticoagulation in cardiac surgery&#44; further efforts are required to identify better pain control to ensure better patient outcomes&#46;</p></span></span>"
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          "titulo" => "INTRODUCTION"
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          "titulo" => "MATERIALS AND METHODS"
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              "titulo" => "Anesthesia and surgical procedures"
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              "titulo" => "Ventilatory and pain score evaluation"
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              "titulo" => "Sample size and statistical analysis"
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        3 => array:3 [
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          "titulo" => "RESULTS"
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              "identificador" => "cesec70"
              "titulo" => "Gas exchange and Spirometric Analysis"
            ]
            1 => array:2 [
              "identificador" => "cesec80"
              "titulo" => "Pain scores&#44; morphine consumption&#44; and plasma concentrations"
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          "titulo" => "DISCUSSION"
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          "titulo" => "REFERENCES"
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    "pdfFichero" => "main.pdf"
    "tienePdf" => true
    "fechaRecibido" => "2008-10-28"
    "fechaAceptado" => "2008-12-09"
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          "palabras" => array:4 [
            0 => "Respiratory mechanics"
            1 => "Gas exchange"
            2 => "Cardiac surgery"
            3 => "Pain scores"
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    "resumen" => array:1 [
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        "resumen" => "<span id="ceabs10" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle10">OBJECTIVES&#58;</span><p id="spara70" class="elsevierStyleSimplePara elsevierViewall">To evaluate the effects of intrathecal morphine on pulmonary function&#44; analgesia&#44; and morphine plasma concentrations after cardiac surgery&#46;</p></span> <span id="ceabs20" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle20">INTRODUCTION&#58;</span><p id="spara80" class="elsevierStyleSimplePara elsevierViewall">Lung dysfunction increases morbidity and mortality after cardiac surgery&#46; Regional analgesia may improve pulmonary outcomes by reducing pain&#44; but the occurrence of this benefit remains controversial&#46;</p></span> <span id="ceabs30" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle30">METHODS&#58;</span><p id="spara90" class="elsevierStyleSimplePara elsevierViewall">Forty-two patients were randomized for general anesthesia &#40;control group n&#61;22&#41; or 400 &#956;g of intrathecal morphine followed by general anesthesia &#40;morphine group n&#61;20&#41;&#46; Postoperative analgesia was accomplished with an intravenous&#44; patient-controlled morphine pump&#46; Blood gas measurements&#44; forced vital capacity &#40;FVC&#41;&#44; forced expiratory volume &#40;FEV&#41;&#44; and FVC&#47;FEV ratio were obtained preoperatively&#44; as well as on the first and second postoperative days&#46; Pain at rest&#44; profound inspiration&#44; amount of coughing&#44; morphine solicitation&#44; consumption&#44; and plasma morphine concentration were evaluated for 36 hours postoperatively&#46; Statistical analyses were performed using the repeated measures ANOVA or Mann-Whiney tests &#40;&#42;p&#60;0&#46;05&#41;&#46;</p></span> <span id="ceabs40" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle40">RESULTS&#58;</span><p id="spara100" class="elsevierStyleSimplePara elsevierViewall">Both groups experienced reduced FVC postoperatively &#40;3&#46;24 L to 1&#46;38 L in control group&#59; 2&#46;72 L to 1&#46;18 L in morphine FEV<span class="elsevierStyleInf">1</span> &#40;p&#61;0&#46;085&#41;&#44; group&#41;&#44; with no significant decreases observed between groups&#46; The two groups also exhibited similar results for FEV<span class="elsevierStyleInf">1</span>&#47;FVC &#40;p&#61;0&#46;68&#41; and PaO<span class="elsevierStyleInf">2</span>&#47;FiO<span class="elsevierStyleInf">2</span> ratio &#40;p&#61;0&#46;08&#41;&#46; The morphine group reported less pain intensity &#40;evaluated using a visual numeric scale&#41;&#44; especially when coughing &#40;18 hours postoperatively&#58; control group&#61; 4&#46;73 and morphine group&#61; 1&#46;80&#44; p&#61;0&#46;001&#41;&#46; Cumulative morphine consumption was reduced after 18 hours in the morphine group &#40;control group&#61; 20&#46;14 and morphine group&#61; 14&#46;20 mg&#44; p&#61;0&#46;037&#41;&#46; The plasma morphine concentration was also reduced in the morphine group 24 hours after surgery &#40;control group&#61; 15&#46;87 ng&#46;mL<span class="elsevierStyleSup">&#8722;1</span> and morphine group&#61; 4&#46;08 ng&#46;mL<span class="elsevierStyleSup">&#8722;1</span>&#44; p&#61;0&#46;029&#41;&#46;</p></span> <span id="ceabs50" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle50">CONCLUSIONS&#58;</span><p id="spara110" class="elsevierStyleSimplePara elsevierViewall">Intrathecal morphine administration did not significantly alter pulmonary function&#59; however&#44; it improved patient analgesia and reduced morphine consumption and morphine plasma concentration&#46;</p></span>"
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            "titulo" => "INTRODUCTION&#58;"
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            "titulo" => "METHODS&#58;"
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          "en" => "<p id="spara10" class="elsevierStyleSimplePara elsevierViewall">PO<span class="elsevierStyleInf">2</span>&#47;FIO<span class="elsevierStyleInf">2</span> ratio between groups&#44; p&#61; 0&#46;078 &#40;means &#177; DP&#41;&#46; P&#46;O&#46;D&#46; &#61; postoperative day&#46; ANOVA&#44; &#42;p&#60;0&#46;05</p>"
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          "en" => "<p id="spara20" class="elsevierStyleSimplePara elsevierViewall">Intensity of Pain between groups &#40;means &#177; SEM&#41;&#46; A&#46; Pain at rest &#40;p-value at 12&#44; 18&#44; 24&#44; and 36h was 0&#46;0095&#59; 0&#46;0013&#59; 0&#46;0089&#59; 0&#46;0446&#44; respectively&#41;&#46; B&#46; Pain upon profound inspiration &#40;p-values were 0&#46;0291&#59; 0&#46;0005&#59; 0&#46;0004&#44; respectively&#41;&#46; C&#46; Pain upon cough &#40;p-values at 12&#44; 18&#44; 24&#44; and 36 hours were 0&#46;0019&#59; 0&#46;0010&#59; 0&#46;0218&#59; 0&#46;0145&#46; - Mann-Whitney Test&#44; p&#60;0&#46;05&#41;</p>"
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          "en" => "<p id="spara30" class="elsevierStyleSimplePara elsevierViewall">Cumulative morphine consumption between groups &#40;means &#177; SEM&#41;&#46; P-values at 18 and 24 hours were 0&#46;0373 and 0&#46;0283&#44; respectively&#46; Mann-Whitney Test&#44; &#42;p&#60;0&#46;05</p>"
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          "en" => "<p id="spara40" class="elsevierStyleSimplePara elsevierViewall">Plasma Morphine Levels between groups&#44; p-value&#61;0&#46;029 at 24 hours&#46; Mann-Whitney&#44; &#42;p&#60;0&#46;05</p>"
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                  \t\t\t\t  " align="left" valign="middle" scope="col">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="center" valign="middle" scope="col">Morphine&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="center" valign="middle" scope="col">p-value&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="center" valign="top">16&#58;04&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="center" valign="top">0&#46;313<a class="elsevierStyleCrossRef" href="#tfn1">&#42;</a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
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                  \t\t\t\t  " align="center" valign="top">60&#46;9 &#177; 7&#46;6&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="top">BMI &#40;Kg&#47;cm<span class="elsevierStyleSup">2</span>&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">27&#46;1 &#177; 3&#46;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">24&#46;4 &#177; 3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="center" valign="top">0&#46;071<a class="elsevierStyleCrossRef" href="#tfn2">&#42;&#42;</a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="top">Higgins Surgical Risk Scale &#40;0&#8211;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">1&#46;727 &#177; 1&#46;08&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">2&#177;1&#46;21&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">0&#46;546<a class="elsevierStyleCrossRef" href="#tfn2">&#42;&#42;</a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">Surgery Duration &#40;min&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">392&#46;5 &#177; 70&#46;30&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">379&#44;5 &#177; 91&#44;00&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">0&#46;606<a class="elsevierStyleCrossRef" href="#tfn2">&#42;&#42;</a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">Tracheal Extubation Time &#40;min&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">396&#46;5 &#177; 234&#46;20&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">349&#46;1&#177; 175&#46;10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">0&#46;466<a class="elsevierStyleCrossRef" href="#tfn2">&#42;&#42;</a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">CPB Time &#40;min&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">98&#46;27 &#177; 26&#46;90&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">95&#46;55 &#177; 38&#46;26&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">0&#46;790<a class="elsevierStyleCrossRef" href="#tfn2">&#42;&#42;</a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">Minimal Temperature at CPB &#40;&#176;C&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">31&#46;30 &#177; 2&#46;70&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">30&#46;68 &#177; 2&#46;66&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="center" valign="top">0&#46;456<a class="elsevierStyleCrossRef" href="#tfn2">&#42;&#42;</a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">Total Dose of Sufentanil &#40;&#956;g&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">257&#46;77 &#177; 81&#46;41&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">200&#46;87&#177; 55&#46;11&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">0&#46;012<a class="elsevierStyleCrossRef" href="#tfn2">&#42;&#42;</a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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            0 => array:3 [
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              "identificador" => "tfn2"
              "etiqueta" => "&#42;&#42;"
              "nota" => "<p class="elsevierStyleNotepara" id="cenpara20">Independent T Samples Test</p>"
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          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spara50" class="elsevierStyleSimplePara elsevierViewall">Sex&#44; Age&#44; IMC&#44; Higgins Surgical Risk Scale&#44; Extubation time&#44; Surgical time&#44; Extracorporeal duration&#44; Minimal temperature at Extracorporeal Circulation between groups&#46; Total dose of sufentanil&#46; Values represent means &#177; SD&#46; <a class="elsevierStyleCrossRef" href="#tfn1">&#42;</a>Chi-square Test <a class="elsevierStyleCrossRef" href="#tfn2">&#42;&#42;</a>Independent T-student Test&#44; p &#60; 0&#46;05</p>"
        ]
      ]
      5 => array:7 [
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                  \t\t\t\t  " align="center" valign="middle" scope="col">Pre-op&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="center" valign="top">1&#46;45&#177;0&#46;60&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="center" valign="top">1&#46;38&#177;0&#46;53&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="center" valign="top">0&#46;0679&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="center" valign="top">2&#46;72&#177;0&#46; 68&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="center" valign="top">1&#46;18&#177;0&#44;45&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="center" valign="top">1&#46;26&#177;0&#46;42&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="top">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="center" valign="top">2&#46;41&#177;0&#46;73&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="center" valign="top">1&#46;06&#177;0&#46;46&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="center" valign="top">1&#46;02&#177;0&#46;54&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="center" valign="top">0&#46;085&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="top">Morphine Group&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="center" valign="top">1&#46;96&#177;0&#46;64&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="center" valign="top">0&#46;90&#177;0&#46;32&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="center" valign="top">0&#46;95&#177;0&#46;26&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="top">Control Group&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="center" valign="top">0&#46;75&#177;0&#46;11&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="center" valign="top">0&#46;79&#177;0&#46;35&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="top">Morphine Group&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">0&#46;74&#177;0&#46;14&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">0&#46;77&#177;0&#46;14&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="center" valign="top">0&#46;78&#177;0&#46;15&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="top">&nbsp;\t\t\t\t\t\t\n
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                  """
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          "en" => "<p id="spara60" class="elsevierStyleSimplePara elsevierViewall">Forced Vital Capacity &#40;FVC&#41;&#44; Forced Expiratory Volume in the First Second &#40;FEV1&#41;&#44; and FEV1&#47;FVC ratio at preoperative&#44; and first and second postoperative days &#40;P&#46;O&#46;D&#46;&#41; &#42;ANOVA&#44; p&#60; 0&#46;05</p>"
        ]
      ]
    ]
    "bibliografia" => array:2 [
      "titulo" => "REFERENCES"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "cebibsec10"
          "bibliografiaReferencia" => array:33 [
            0 => array:3 [
              "identificador" => "bib1"
              "etiqueta" => "1"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Intraoperative and postoperative risk factors for respiratory failure after coronary bypass"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => """
                              CC Canver \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              J Chanda \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/s0003-4975(02)04493-4"
                      "Revista" => array:6 [
                        "tituloSerie" => "The Annals of thoracic surgery"
                        "fecha" => "2003"
                        "volumen" => "75"
                        "paginaInicial" => "853"
                        "paginaFinal" => "857"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12645706"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            1 => array:3 [
              "identificador" => "bib2"
              "etiqueta" => "2"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Three-year survival after four major post-cardiac operative complications"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => """
                              OV Hein \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              J Birnbaum \n
                              \t\t\t\t\t\t\t\t
                              """
                            2 => """
                              KD Wernecke \n
                              \t\t\t\t\t\t\t\t
                              """
                            3 => """
                              W Konertz \n
                              \t\t\t\t\t\t\t\t
                              """
                            4 => """
                              U Jain \n
                              \t\t\t\t\t\t\t\t
                              """
                            5 => """
                              C Spies \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1097/01.CCM.0000242519.71319.AD"
                      "Revista" => array:6 [
                        "tituloSerie" => "Critical care medicine"
                        "fecha" => "2006"
                        "volumen" => "34"
                        "paginaInicial" => "2729"
                        "paginaFinal" => "2737"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16971859"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            2 => array:3 [
              "identificador" => "bib3"
              "etiqueta" => "3"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Pulmonary complications after cardiac surgery"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => """
                              C Weissman \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1177/108925320400800303"
                      "Revista" => array:6 [
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Article information
ISSN: 18075932
Original language: English
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2024 June 13 10 23
2024 May 12 11 23
2024 April 13 19 32
2024 March 13 13 26
2024 February 6 7 13
2024 January 9 8 17
2023 December 5 12 17
2023 November 7 19 26
2023 October 11 29 40
2023 September 9 6 15
2023 August 5 3 8
2023 July 2 6 8
2023 June 3 0 3
2023 May 2 2 4
2023 April 3 2 5
2023 March 3 1 4
2023 February 2 1 3
2023 January 2 3 5
2022 December 3 0 3
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es en pt

¿Es usted profesional sanitario apto para prescribir o dispensar medicamentos?

Are you a health professional able to prescribe or dispense drugs?

Você é um profissional de saúde habilitado a prescrever ou dispensar medicamentos