1 BACKGROUND The world's demand for open heart surgery as well as in Viet Nam is huge Early extubation trend after cardiac surgery was born based on balance anesthesia and selecting opioid with short duration of action At the moment, opioid dose is lower than before to meet the needs of the increasing number of open-heart surgery, to reduce the cost of treatment and complications of mechanical ventilation, so the pain after surgery is very important (Roediger, 2004) The effective pain management after heart surgery not only reduces the harmful effects on the cardiovascular, respiratory, immune and coagulation but also helps patients recover faster, and is an indispensable mental care Effective treatment of acute pain may reduce the incidence of chronic pain, improve quality of life (Wu, 2000; MacIntyre, 2010) The discovery of opioid receptors in the dorsal horn opened a new pain control method Morphine is less lipophilic, has slow onset of action, reaching the maximum analgesic effect of the chest after lumbar injection in 4-7 hours, duration of effect lasts up to more than 24 hours so they're suitable for reducing postoperative pain Sufentanil is more lipophilic, has rapid onset of action, less than minutes, the duration of effect lasting 2-6 hours is suitable for pain in surgery The meta-analysis study showed that morphine dose more than 0.3 mg had not increased the analgesic effects but increased undesirable effects (Gehling, 2009) Bettex and Swenson used intrathecal sufentanil of 50 mcg The combination of morphine and intrathecal sufentanil may provide both intraand postoperative analgesia and help patients recover "no pain" and reduce chronic pain after surgery In the world, there are few studies with limited objects, no study has been done on this issue in Viet Nam We conducted this study with the following objectives: To compare the intraoperative analgesia of single intrathecal morphine dose of 0.3 mg, intrathecal morphine 0.3 mg combined without or with sufentanil doses of 25 mcg or 35 mcg dose before induction in patients receiving general anesthesia for open heart surgery To compare postoperative analgesia of the above methods To assess the effects on respiration and some undesirable effects of the methods above THE NEW FINDINGS OF THE THESIS - Intrathecal sufentanil attenuates intraoperative fluctuations of mean blood pressure and heart rate, reduces significantly intraoperative intravenous sufentanil consumption and the intrathecal sufentanil dose of 25 microgram is appropriate to reduce pain during open heart surgery - The intrathecal morphine dose of 0.3 mg combined with or without sufentanil reduces postoperative pain, manifested by the decrease in morphine consumption during the first 30 hours, VAS at rest during the first 16 hours and VAS at deep breath after extubation At this dose of intrathecal morphine, no changes in FEV1 and FVC, in the undesirable effects, in the duration of mechanical ventilation and extubation time are found - The combination of intrathecal morphine and sufentanil before induction in open heart surgery provides effective analgesia per and post-operatively Layout of the thesis: The thesis has 117 pages Background pages Chapter Overview 35 pages Chapter Subjects and Methods 16 pages Chapter Results 26 pages Chapter Discussion 36 pages Conclusions page Recommendation page References: 169 (16 Vietnamese, 136 English, 17 French) CHAPTER OVERVIEW 1.1 Postoperative pain affects the body 1.1.1 Factors affecting postoperative pain Surgery is the main factor to decide the importance and duration of postoperative pain Thoracic and big abdominal surgeries are the most painful In addition to surgical factors, cultural factors, the threshold of pain, previous pain experience, the emotional, cognitive, situations, behaviors and attitudes, age and gender also affect the nociception (Serrie, 2002) 1.1.2 The impact of pain during and after surgery on the body Trauma caused by the surgery causes neuroendocrine response, a combination of the local inflammatory response (due to cytokine and leukotriene) and neuroendocrine metabolic factors causes catabolisme, increase in catabolic hormones such as catecholamines, cortisol, renin, aldosterone and glucagon, decrease in anabolic hormones such as insulin and testosterone On the way to the cortex, pain impulses going to the hypothalamus trigger the behavior, emotion, mood changes and general feeling such as anxiety, sleep disorders When pain lasts longer than normal may cause depression Postoperative pain if not treated effectively is the risk of chronic pain, affecting the quality of life (Wu, 2002) Activation of the sympathetic nervous system in response stress or inadequate analgesia may cause heart rate, myocardial contractility increase and hypertension leading to increased myocardial oxygen consumption, loss oxygen demand - supply balance, leading to an increased risk of myocardial ischemia or infarction that this phenomenon peaks in the postoperative period Influence on respiratory function occurs in the first 24 hours following surgery and returns to the preoperative values in weeks thoracic or big abdominal surgery Reduction is to 40% vital capacity after upper abdominal surgery Besides, There is postoperative increased coagulation status, immunosuppression and gastrointestinal disorders 1.2 Pain assessment 1.2.1 Intraoperative pain assessment Analgesia (pain relief) amnesia (loss of memory) and immobilisation are the three major components of anaesthesia The perception of pain, and the need for analgesia are individual, and the monitoring of analgesia is indirect and, in essence, of the moment Under general anaesthesia, analgesia is continually influenced by external stimuli and the administration of analgesic drugs, and cannot be really separated from anaesthesia: the interaction between analgesia and anaesthesia is inescapable There is no stool or method to directly mesure intraoperative pain Autonomic reactions, such as tachycardia, hypertension, sweating and lacrimation, although non-specific, having been proposed by Evans, using the PRST (blood Pressure, heart Rate, Sweating, Tears) score of responsiveness are always regarded as signs of nociception or inadequate analgesia The authors used this score to assess intraoperative pain in their studies (Stomberg 2001; Turker, 2005; Guignard, 2006) 1.2.2 Postoperative pain assessment There are numerous scales to to assess postoperative pain Currently, there are three types of scale used clinically to assess postoperative pain (Viel, 2007) Visual Analogue Scale (VAS): VAS is a reference scale in assessing the degree of pain and the effectiveness of the treatment Verbal Numeric Rating Scale (VNRS): Scale consists of a sequence of numbers, corresponding to "no pain" and 10 being "unbearable pain" Patients were asked to evaluate and reply with the number corresponding to their level of pain This assessment may not need tools VNRS scale is suitable for elderly patients Categorical rating Scale (CRS): This scale consists of five numbers in ascending order of intensity of pain, each number corresponding to a description; - no pain, - mild, - moderate, - severe, - unbearable pain This method is a quick, simple, low rate of incorrect response This method is especially suitable for patients unable to use VNRS or VAS scale (children and elderly) The authors divide the pain intensity into three degrees: low, VAS ≤ cm, moderate, VAS - cm and severe VAS > cm At the recovery room, patients with limited oral expression, the VAS is the appropriate scale to assess pain and evaluate treatment response and morphine is used if VAS ≥ cm VAS score ≤ cm at rest and ≤ cm at movement are defined as effective pain relief 1.3 Intrathecal opioid for pain management after cardiac surgery 1.3.1 Pain in cardiac surgery In cardiac surgery, the pain is caused by skin incision in the chest, sternotomy, field extension, the mediastinal dissection, vascular canuyn, the subxiphoid drain and blood in pleural cavity This painful stimuli are conveyed mainly by the intercostal nerves from T1 to T11, innervating the chest wall, by diaphragmatic innervating diaphragmatic pleura and by X nerve innervating mediastinal pleura In addition, the cutaneous branches from the cervical superficial plexus coming down to innervate skin upper part of the chest wall (Morgan, 2005) The neural axial (spinal, epidural) and paravertebral techniques may not affect the diaphragmatic nerve, the vagus nerve, which is also the basis for the application of multimodal analgesic method after thoraco-cardiac surgery 1.3.2 Intrathecal opioid analgesia Table 1.5 Pharmacodynamic parameters of intrathecal morphine and sufentanil Drugs Sufentanil Morphine Onset < - hours Peak action < 30 - hours - hours 20,5 - 40 hours Time Duration 1.3.3 Intrathecal opioid analgesia studies in cardiac surgery In 1979, Wang reported the effect of intrathecal morphine in postoperative and cancer analgesia Mathews and Abrahams were the first ones who applied intrathecal morphine on the heart surgery patients The studies before 1990’s used high-dose intrathecal morphine When early extubation was applied in cardiac surgery, the authors have used lower doses of intrathecal morphine so as not to prolong the duration of mechanical ventilation after surgery, the authors used doses from - 10 mcg/kg or 0.5 mg (Jacobsohn, 2006; Roediger, 2006; Yapici, 2008) The recent meta-analysis studies recommended dose of intrathecal morphine ≤ 0.3 mg to reduce undesirable effects In Vietnam, the study by Nguyen Phu Van combined mcg/kg morphine with 1.5 mcg/kg fentanyl intrathecally, Nguyen Van Minh, morphine 0.3 mg combined with sufentanil before induction for open heart surgery shows the effective pain relief Some authors used intrathecal sufentanil dose of 50 mcg The randomized prospective studies on combination of morphine and intrathecal sufentanil are needed CHAPTER SUBJECTS AND METHODS 2.1 Subjects 2.1.1 Selection criteria: Patients were planned open heart surgery to repair or replace valves, to repair congenital abnormalities; Early extubation prediction; Aged 18 - 60; ASA II - III; NYHA I - III; agree to participate in research; No allergy to opioids 2.1.2 Exclusion criteria: Patients with chronic diseases such as chronic lung diseases, liver failure, kidney failure, systolic pulmonary artery pressure > 70 mmHg; previous heart surgery; history of addiction or opioid dependence, taking pain medication before surgery; abnormal spinal anatomy; Local infection or sepsis at the site of lumbar punctur; left ventricular ejection fraction (LVEF) < 50%; history of abnormal bleeding prothrombin ratio < 70%, bleeding disorders, platelet count 0.05) 3.3.3 FVC, FEV1 FVC and FEV1 on the first and second day in the four group were lower than before surgery (p < 0.05) No statistically significant differences between the four groups were found before surgery, on the first and the second day (p > 0.05) 3.3.4 Postoperative hemodynamic changes The difference in heart rate before and after extubation of the groups was not statistically significant (p > 0.05) Mean blood pressure before and after extubation in group was significantly higher than group 2, 3, (p < 0.05) 3.4 Respiratory changes and other undesirable effects 22 Table 3.26 Mechanical ventilation and extubation time (hour) Group Group Group Group (n = 40) Time Group (n = 40) (n = 40) (n = 40) p Ventilation 4,98 ± 3,55 4,26 ± 2,29 4,66 ± 2,46 4,54 ± 2,01 (min - max) (0,5 - 16,0) (1,0 - 12,0) (1,5 - 12,0) (1,0 - 9,0) > 0,05 Average 4,59 ± 2,61 hours Extubation 7,21 ± 3,93 6,39 ± 2,80 6,97 ± 2,51 6,70 ± 2,13 (min - max) (1,0 - 17,0) (2,5 - 14.0) (2,0 - 13,0) (1,5 - 12,0) > 0,05 Average 6,82 ± 2,89 hours Mechanical ventilation and extubation time did not differ significantly between groups (p > 0,05) Table 3.32 Other undesirable effects Group Group Group Group (n = 40) (n = 40) Nausea (22,5%) 10 (25%) (22,5%) 8(20%) > 0,05 Vomiting (17,5%) (12,5%) 6(15%) (17,5%) > 0,05 Variable (n = 40) Group (n = 40) P 23 Pruritus Headache (7,5%) (5%) (7,5%) (10%) > 0,05 (5%) (2,5%) (5%) (7,5%) > 0,05 The difference of nausea, vomiting, pruritus, headache incidence between groups was not statistically significant (p > 0.05) The rate of nausea incidence in the range of 20 - 22%, nausea 12.5 - 17.5%, pruritus 10%, headache 2.5 - 7.5% 24 CHAPTER DISCUSSION 4.1 Patient, anesthesia and surgery characteristics 4.1.1 General characteristics Age, gender, height, weight, ASA and NYHA between groups were not significantly different, which proves the identity of the participants in the study group 4.1.2 Anesthesia, surgery and cardiopulmonary bypass characteristics In this study, early extubation anesthesia protocol used at national and international cardiac center was applied Almost 70% patients underwent valve replacement or repair Surgical, aortic clamp and cardiopulmonary bypass time between the groups did not differ significantly 4.2 Intraoperative analgesia 4.2.1 Intraoperative sufentanil consumption and anesthesia time Anesthesia time between the groups were similar but the amount of sufentanil in group and group (with intrathecal sufentanil) were lower than group and group (without intrathecal sufentanil) in a statistically significant manner (p < 0.05) This proves that intrathecal sufentanil used before induction provides intraoperative analgesia This result is consistent with findings of other authors, Swenson (1994), Bettex (2000), Nguyen Phu Van (2004) 4.2.2 Intraoperative mean blood pressure and heart rate stability 25 Intrathecal sufentanil has rapid onset of action so it is suitable for intraoperative analgesia Time from spinal injection to intubation between the groups were similar, about - 10 minutes, at this time sufentanil does not achieve the maximum effect, helping to avoid the itching, nausea for patients if available Intrathecal sufentanil does not inhibit response to intubation The stimuli from laryngopharyngal area during laryngoscopy and bronchial stimulation during tube placement are transmissed by nerves X, so lumbar intrathecal sufentanil injection has little inhibitory effect on those stimulation, Swenson (1994) Time from spinal injection to the skin incision about 50 minutes, at this point, intrathecal sufentanil has maximum effect and as a result, patients in the groups with intrathecal sufentanil had less response of the heart rate and mean blood pressure increase at the skin incision than patients who did not receive intrathecal sufentanil (graph 3.1 and graph 3.2) The important thing is that good intraoperative analgesia of intrathecal sufentanil shows blood pressure and heart rate stability at the most painful time in surgery The percentage of patients with mean blood pressure increase in group and group were significantly higher than in group and group (Table 3.12, 3.14) Thus, intrathecal sufentanil before induction provided intraoperative effective analgesia, manifested by intravenous sufentanil dose reduction, heart rate and mean blood pressure stability at the most painful time in surgery This stability is significant for reducing manipulations of analgesic and anesthetic level which may lead to hemodynamic fluctuations, this is significant in general anesthesia for surgery and anesthesia for heart surgery in particular 26 Selecting the appropriate dose of sufentanil is also a matter of concern High-dose sufentanil of 150 mcg provides good pain relief but needed postoperative mechanical ventilation, prolonged extubation time (Borgdorff, 2004) In contrast, low doses of sufentanil, 10 mcg, did not increase the analgesic effect of intrathecal morphine 0.4 mg in patients undergoing colorectal surgery (Culebras, 2007) In addition, high doses of subarachnoidal sufentanil may risk neurological toxicity Rawal (1991) showed that sufentanil dose of 150 240 mcg caused histopathological changes in sheep spinal cord On the other hand, Sabbe (1994) found no evidence of neurological toxicity by analysis of cerebrospinal fluid and spinal cord histopathology after injecting intrathecally sufenatnil doses of 5, 25, 50 mcg several days Therefore, the authors recommend not to use the dose of intrathecal sufentanil more than 50 mcg In this study, we found the amount of intravenous sufentanil and the percentage of patients who had mean blood pressure and heart rate increase of more than 20% above the baseline of intrathecal sufentanil 25 mcg and 35 mcg were similar According to the Practical Guide of the American Anesthesiology, the lowest effective dose is chosen So, the intrathecal sufentanil dose of 25 microgram is appropriate to reduce pain during open heart surgery 4.3 Postoperative analgesia 4.3.1 Postoperative intravenous morphine consumption Research results showed that patients in intrathecal morphine groups had consumed the amount of intravenous morphine consumption by PCA at all time points after surgery less than the patients in the control 27 group (p < 0.05) (figure 3.4) While comparing morphine consumption on day 1, 2, 3, there was a difference between the groups on the first and second day (p < 0.05), (table 3.16) When comparing the amount of morphine intravenously every hours, the results showed that intrathecal morphine had reduced intravenous morphine consumption through a PCA to the 30th hour in comparison with group control (p < 0.05) The consumption morphine in the first hours in group was statically significantly higher than in group and group (p < 0.05) Research results are consistent with research of the other authors Alhashemi (2000), Roediger (2006), Yapici (2008), Dos Santos (2009) 28 4.3.2.VAS pain score during postoperative days VAS pain scores at rest in intrathecal morphine group (group 2, 3, 4) were statistically significantly lower than control group (group 1) during the first 16 hours after surgery (p < 0.05) and those VAS were less than in all the time points, VAS pain scores in the control group at the H4, H8, H12 were higher than in group (table 3.18) VAS pain score at deep breath in intrathecal morphine groups was statistically significantly lower than control group after extubation (p < 0.05), but no statistically significantly on day and day after surgery (p > 0.05) VAS at deep breath in the intrathecal group was less than (Graph 3.3) Effective pain relief when patients waking up in the recovery room is very important Nader (2000) showed that patients given intrathecal morphine mcg/kg and fentanyl 1.5 mcg/kg had low VAS pain score (two versus seven) when entering to the recovery room and 24 hours after surgery (3 versus 5) versus the control group (p < 0.05) 4.3.3 FVC and FEV1 Although intrathecal opioid groups (group 2, group and group 4) had better analgesia than the control group (group 1), but there was no statistically significant difference between the groups of FVC, FEV1 There was no difference in FVC and FEV1, this can be explained that patients group used morphine via PCA, this is also effective pain relief method Furthermore, postoperative pulmonary dysfunction is a complex process affected by many factors including reduced normal activity of the respiratory muscles due to anesthesia, 29 surgery, spinal inhibitory reflex (spinal reflex inhibition ) on neural activity of the diaphragmatic nerve and respiratory muscles Effective pain relief after surgery is only one part of improved respiratory function, good heart function is also very important to improve respiratory function, oxygen exchange in the lungs and muscle activity (Warner, 2000 ) In conclusion, there is no improvement in FCV and FEV1 in intrathecal morphine versus the control group 4.3.4 Postoperative mean blood pressure and heart rate stability The differences of postoperative heart rate and mean blood pressure between groups were not statistically significant Mean blood pressure at hours after surgery in group was significantly higher than in group 2, group and group (p > 0.05) At this time, anesthetic drugs used intraoperatively was off, intrathecal morphine had achieved maximum effect so patients in those groups felt less pain Heart rate after surgery between the groups was not statistically significant difference (p > 0.05) and higher than the baseline value, then the heart rate decreased 4.3.5 Choosing the appropriate dose of intrathecal morphine Due to respiratory depression and prolongation of mechanical ventilation when using high doses of intrathecal morphine, the authors used a lower dose of morphine in early extubation anesthesia in the recent times The authors selected doses of mcg/kg or 0.5 mg (Alhashemi, 2000; Casalino, 2006; Weismann, 2012) Meanwhile, Lena (2003) concluded that a dose of mcg/kg is not effective enough to ease the pain for heart surgery patients The current trend, doses of - 10 mcg/kg were used (Jacobsohn, 2005; Turker, 2005) There has not been any studies indicating the optimal dose For pain relief after cardiac surgery, the authors 30 selected the morphine dose mcg/kg (Nguyen Phu Van, 2000; Zisman, 2005; Yapici, 2008) Patient of average weight 49.4 ± 6.8 kg, if morphine dose mcg/kg to about 0.3 mg, to facilitate the drug preparation, we chose a dose of 0.3 mg This dose is also consistent with the recommendations of other authors It provides effective analgesia but not increases undesirable effects (Rathmell, 2005; Gehling, 2009) 4.4 Respiratory changes and other undesirable effects 4.4.1 Mechanical ventilation and extubation time Differences in extubation time between groups were not statistically significant (p > 0.05) and overall average 6.82 ± 2.89 hours, in line with the early extubation trend after cardiac surgery Intrathecal morphine 0.3 mg combined with or without sufentanil did not prolonged mechanical ventilation after surgery, but it did not shorten the extubation time 4.4.2 Respiratory rate, SpO2 before and after extubation Respiratory rate after extubation in group and group were significantly higher than before extubation (p < 0.05), but these parameters are within acceptable limits After surgery and cardiopulmonary bypass, the tidal volume decreases due to atelectasis, the body increase the respiratory rate Differences in SpO2 between the groups was not statistically significant (p > 0.05) 4.4.3 Respiratory rate, SpO2 during days after surgery 31 Respiratory rate during the 72 hours after after surgery of four groups did not differ significantly, no case had respiratory rate less than 12 breaths/min SpO2 at the different time points after surgery did not differ between the four groups, and no case had SpO2 below 92% 4.4.4 Other undesirable effects The nausea and vomiting incidence of the four group were similar, nausea 20 - 22%, vomiting 12.5 17.5% This rate is equivalent to the study of Mangia (2007), the authors used intrathecal morphine 14 mcg / kg plus fentanyl 50 mcg and showed that the incidence of vomiting in the study group was 19% and the control group 23% Pruritus was low (5-10%), there was no statistically significant difference between the groups (Table 3.32) Urinary retention: In this study, the urinary catheter was usually drawn on the second day, at this time, urinary retention effects of opioids was off, the urinary retention incidence was low and did not differ between the groups (p > 0.05) CONCLUSIONS Intraoperative analgesia - Intrathecal morphine did not have intraoperative analgesia: the intrathecal morphine and the control group did not differ significantly in the intravenous sufentanil consumption, mean blood pressure, heart rate 32 - Intrathecal sufentanil provided effective intraoperative analgesia: Significantly intravenous sufentanil dose decrease and blood pressure and heart rate stability after skin incision in both groups using sufentanil (25 mcg and 35 mcg dose) in comparison with the two groups not using intrathecal sufentanil (p < 0.05) - Intrathecal sufentanil dose of 25 mcg and 35 mcg had similar effects, the intrathecal sufentanil dose of 25 microgram is appropriate to reduce pain during open heart surgery Postoperative analgesia - The intrathecal morphine combined with or without sufentanil groups had a better postoperative analgesia than the control group: Reduction in morphine consumption in the first 30 hours, VAS pain scores at rest during the first 16 hours and VAS pain at deep breath after extubation - When combined with morphine, intrathecal sufentanil dose of 25 mcg and 35 mcg (groups and 4) had the same pain relief after surgery, however, only in the first hours Respiratory changes and undesirable effects - Mechanical ventilation, extubation time and FVC and FEV1 was not affected whether using intrathecal morphine used alone or in combination with sufentanil - Undesirable effects did not differ significantly between groups and with mild and low incidence RECOMMENDATIONS 33 Through research, we found a number of issues need to be studied further: Effects as well as the appropriate dose of intrathecal morphine in pain management after thoracic surgery The chronic pain incidence of intrathecal opioid and other pain relief methods currently applied Determination of the morphine and sufentanil concentration in cerebro-spinal fluid at different dose 34 24,1,2,23,22,3,4,21,20,5,6,19,18,7,8,17,16,9,10,15,14,11,12,13 ... of multimodal analgesic method after thoraco-cardiac surgery 1.3.2 Intrathecal opioid analgesia Table 1.5 Pharmacodynamic parameters of intrathecal morphine and sufentanil Drugs Sufentanil Morphine... Group 2: Group injected intrathecal morphine 0.3 mg Group 3: intrathecal morphine 0.3 mg plus sufentanil 25 mcg Group 4: intrathecal morphine 0.3 mg plus sufentanil 35 mcg 2.2.3 The main criteria... Intraoperative sufentanil consumption and anesthesia time * † *, † p < 0,05: Versus group and Figure 3.1 Intraoperative sufentanil consumption and anesthesia time 13 Anesthesia time did not differ