5067300-190500Text 00Text Introduction

5067300-190500Text
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Introduction:
Scoliosis surgery aims to correct the curvature, improve posture and reduce progression of respiratory dysfunction. It can result in a big amount of blood loss due to rich venous plexus and a large raw area of decorticated bony tissue which may be more than the patient’s blood volume 1
Exposure to allogeneic blood transfusions can be lessened by procedures to limit blood loss. Simple measures included careful positioning to avoid inferior vena cava compression, preventing hypothermia, correction of coagulation disorders, controlled hypotension and good surgical technique 2
The utilization of antifibrinolytics has come into support for cardiovascular and orthopedic surgery where blood loss is of noteworthy concern. These incorporate aprotinin, tranexamic acid (TXA), and epsilon aminocaproic acid (EACA). Aprotinin is a serine protease inhibitor with antifibrinolytic properties. Conversely, TXA and EACA are engineered lysine analogs that go about as inhibitors of fibrinolysis. TXA is ten times more powerful than EACA and ties more firmly to the plasminogen molecule. 3
We have as of late detailed that TXA summons pain in rats by repressing GABA and glycine receptors on the spinal dorsal horn neurons 4.

This proposes TXA can possibly bring out pain and increment the requirement for higher measurements of analgesics during surgery. In any case, there are no reports on whether TXA provokes intraoperative nociception.

We speculated that TXA would provoke pain in patients experiencing surgery for adolescent idiopathic scoliosis (AIS), and along these lines, in the present study, we assessed the amount of intraoperative fentanyl boluses consumption during AIS surgery in patients treated with different doses of TXA.

TXA has been appeared to diminish seizure edge in patients experiencing heart surgery 5.

It likewise has the hypothetical danger of thromboembolic illness, despite the fact that a current efficient survey of randomized trials demonstrated thromboembolic difficulties to be exceptionally uncommon 6
The normal utilization of TXA for young people and grown-ups experiencing back spinal combination for spinal disfigurement has turned into the standard of care at a few organizations. Notwithstanding, there remains a scarcity of uniform information as regards to the perfect dose and timing of TXA without developing adverse effects.
Therefore, the objective of this prospective, randomized, double-blind study was to evaluate the effect of TXA on analgesic requirements in adolescent patients undergoing elective single stage posterior spine fusion surgery for idiopathic scoliosis
Subjects and Methods:
After the endorsement of the Hospital Ethical Committee and written informed consent were obtained, the study was conducted on 60 patients with American Society of Anesthesiologists (ASA) physical status I and II, of either sex, 12-18 years of age, who were scheduled for elective single stage posterior spine fusion surgery for idiopathic scoliosis under general anesthesia.
This work has been carried out in accordance with The Code of Ethics of the World Medical Association (Declaration of Helsinki) for experiments involving humans.

Patients known to have renal or hepatic disorder, bleeding diathesis, thromboembolic event 1 year prior to surgery, preoperative anemia (hemoglobin ; 11 g/dL in females; hemoglobin ; 12 g/dL in males), preoperative platelet count ; 150,000/mm3, International Normalized Ratio (INR) ; 1.4 and history of uncontrolled hypertension were dismissed from the study.
Additionally, patients with neuromuscular disease, congenital or syndromic scoliosis or surgery performed via either combined anterior and posterior spinal fusions or the anterior procedure are excluded. Severe pulmonary disease, i.e., FEV1 ; 50% normal were also excluded from the study.

If intraoperative surgical complications such as uncontrollable surgical bleeding from broken vertebral lamina, or dural tears, etc. occurred, the patients were excluded from the study.

Besides, all the patients had undergone MRI before the surgery, and were affirmed to have no intraspinal malformations such as syringomyelia, split cord, and tethered cord. The procedures were performed by the same team of orthopedic surgeons and anesthesiologists at Ain Shams university hospital- Assembled Theater – Orthopedics operating rooms between April 2017 and November 2017. This trial was a prospective, randomized, double-blinded study.

The patients were arbitrarily allocated into three equivalent groups (25 each):
Group C (control): patients received normal saline.

Group HD (High Dose): patients received tranexamic acid with a loading dose of 50 mg/kg of body weight, given over 30-minute period before the skin incision. After the incision has been made, continuous infusion is maintained at the rate of 20 mg/kg/h until the end of the operation, and skin closure.

Group LD (Low Dose): patients received tranexamic acid with a loading dose of 10 mg/kg of body weight, given over 30-minute period before the skin incision, continual infusion is maintained at the rate of 1 mg/kg/h until the end of the procedure and skin closure.

The dosing regimen is also in accordance with existing guidelines 7-10. As discussed above, TXA has a 30-year safety history in the cardiac literature and both high and low doses have been used securely in pediatric and adult spinal deformity patients.

All patients were admitted to Ain Shams university hospital one day before the operation. Preoperative visit was directed to explain the maneuver, history taking and check the investigations. Relevant investigations included hemoglobin level, total count, differential count, liver function tests, renal function tests, serum electrolytes, coagulation profile, random blood sugar, electrocardiogram (ECG), CXR, pulmonary function test and echocardiogram.

In the pre-anesthetic room, IV line was inserted and midazolam 0.01-0.2 mg/kg was administrated.

General anesthesia was induced by propofol 2 mg/kg, fentanyl 1 ?g/kg, and tracheal intubation was facilitated by atracurium 0.5 mg/kg.
After intubation the patient was positioned prone, ensuring that the eyes, nose and abdomen were free and there was no undue compression to the vessels or hindrance to respiration.

Anesthesia was maintained by isoflurane 1-2 MAC and top up doses of atacurium 0.1 mg/kg every 20 minutes. Respiratory parameters were acclimated to keep the end tidal CO2 between 35-40 mmHg.

To control the patients’ intraoperative nociception, fentanyl was infused constantly at a rate of 0.5 ?g/kg/ h to maintain the heart rate (HR) and blood pressure (BP) fluctuations within 20% of the baseline values. The baseline values were determined at the start of the surgery and were kept to levels similar to those determined the day before surgery with the patient in the supine position at rest. If the HR and BP increased by more than 10% of the baseline values, the anesthesiologist gives a bolus dose of fentanyl 25 ?g. Whenever systolic blood pressure (SBP) decreased to <80 mmHg, ephedrine was administered.

Mean arterial pressure (MAP) was maintained at 70 mmHg during the dissection phase until spine was exposed (using isoflurane % titration), and MAP was raised to 90 mmHg during the correction phase of surgery. Transfusion threshold was not rigidly defined. Transfusion threshold relied upon the anesthesiologist’s and surgeon’s decision and on patient’s comorbidities.

All patients had undergone posterior spinal fusion with instrumentation. Basically, the surgical technique involved a skin incision on the midline above the spinal processes, followed by dissection of the soft tissues till the vertebrae are exposed. Careful hemostasis was embraced. The ligaments and facets were released in order to gain spinal mobility. Pedicle screws were placed on both sides of the pedicle in the fusion area except for thin pedicles. All facet joints were excised, and Ponte osteotomy was performed if necessary. A correction maneuver for scoliosis was performed via in situ bending with or without the rod derotation technique. After decortication of the lamina, morselized local bone grafts and artificial bone grafts packed throughout the instrumented area. No iliac crest bone grafts were used.

After wake test performance, a single bolus dose of 5 mg morphine was given with subsequent stopping of the fentanyl infusion shortly after 30 minutes from morphine’s administration
Intraoperative monitoring included noninvasive blood pressure (NIBP), ECG, pulse oximetry, capnography, temperature, and urine output. Maintenance fluid requirements and third-space losses were replaced with balanced crystalloid solutions
The following parameters were recorded:
– Demographic characteristics (Age, sex, height, weight, BMI and ASA physical status.)
– Time of surgery (time from skin incision till removal of surgical drapes)
– Total consumption of intraoperative fentanyl boluses
– The heart rate, systolic blood pressure (SBP), diastolic blood pressure (DBP) were recorded preoperatively and at 5 min, 10 min, 15 min, 20 min, 30 min, 45 min, 60 min, 75 min, 90 min, and 120 min following induction of anesthesia.

– The total amount of blood loss intraoperative was measured by adding the volume of blood in the suction bottles to the weight of gauze.

– Complications such as myocardial ischemia (MI), acute renal failure, stroke, seizure, deep vein thrombosis (DVT) and pulmonary embolism (PE) in the perioperative period were recorded (During 1st postoperative day only).

Patients were extubated at the end of surgery and observed in the postanesthesia care unit (PACU).

We defined the primary outcome as the total dose given of intraoperative fentanyl. Top up dose of fentanyl given was based on the patient’s vital signs, such as HR and BP, which reflect the level of intraoperative nociception being experienced by the patient. We considered that the top up doses of fentanyl during the surgery reflected the degree of intraoperative nociception as a way to determine whether TXA evoked pain.

Secondary outcomes were: intraoperative blood loss, time of surgery and perioperative complications.

Statistical analysis used:
The primary outcome to be used in the sample size calculation is the dose of analgesic needed during the operation).  A sample size of 75 cases (25 cases per group) is satisfactory to detect an effect size of 0.4 (a medium effect size) using omnibus ANOVA test with level of significance of 0.05 and power of 0.80.

Data were analyzed using SPSS 21.0 for Windows (SPSS, Chicago, IL, USA). Analysis of variance was used to compare the three groups for quantitative parametric data with post-hoc Tukey’s test performed if there was a significant difference among the groups .Chi square test was used for comparison of qualitative data. Continuous parametric data was presented as mean± SD and categorical data was presented as number of patients. P-values of <0.05 were considered significant.

Results:
No differences in patients’ characteristics were observed between the 3 groups. Also, regarding the surgical data, no statistically significant differences were observed in the preoperative Cobb angle or preoperative pulmonary function tests (Table 1)
Table (1): Patients’ characteristics in the 3 study groups.

Data are presented as mean ± SD or ratio
PFT= Pulmonary function test
Group C (n=25) Group LD
(n=25) Group HD (n=25) p-value
Age in years
14.6± 2.16 14.6 ± 2.1 14.68± 2.07 0.988
Sex
Male/Female 11/14
Male = 44%
Female = 56% 11/14
Male = 44%
Female = 56% 10/15
Male = 40%
Female = 60% 0.947
Body weight in kg
39.4±4.3 39± 3.97 39.1 ± 2.5 0.993
ASA
I / II 16/9 14/11 15/11 0.8
Cobb’s angle 43.6º ± 3.69 43.6 º ± 3. 69 43.8 º ± 3.62 0.975
PFT
Normal/Mild restrictive 21/4 21/4 21/4 1
Moreover, no significant differences in the hemodynamic parameters were observed between the 3 groups at any of the examined time points (Figure 1, 2, 3)

On the other hand, surgery and anesthesia durations were significantly shorter, and the total blood loss was significantly lower in a dose dependent manner of tranexamic acid. One can notice that HD group showed shortest surgical duration (mean of 128 min; p ; 0.001) ; least blood loss (mean of 181ml; p ; 0.001) when compared to the LD group and control group.

Also, the LD group when compared with the control group showed significant shorter duration (mean of 188 min versus 208 min respectively) ; lesser blood loss (mean of 229 ml versus 266 ml respectively) (Table 2).

Patients in the HD group received highest doses of fentanyl than those in the LD group (mean of 60 µg versus 27 µg respectively). The control group almost received no extra intraoperative narcotic doses. (Table 2)
Table (2): Surgical time. Intraoperative blood loss and intraoperative fentanyl consumption
Group C (n=25) Group LD (n=25) Group HD (n=25) p-value
Surgical time in minutes 208.33±21.1 188± 13.41 128.3± 7.6 ; 0.001 *
Blood loss in milliliter 266.7±42.4 229± 22.44 181.25± 18.7 ; 0.001 *
Fentanyl in microgram 0 27± 17.6 60.5± 12.5 ; 0.001 *
Data are presented as mean ± SD or ratio
P;0.001 is considered statistically significant
None of the patients showed any clinical signs of intraoperative or postoperative complications associated with the use of tranexamic acid such as seizures and deep venous thrombosis. Moreover, none of the patients in either group received blood transfusion during surgery.

Discussion:
The normal utilization of TXA for patients experiencing spinal fixation for spinal distortion has turned into the standard of care lately .However, the perfect dosage and timing of TXA organization hasn’t been characterized yet.

Both HIGH and LOW dosages of TXA have been used securely for a long time in the cardiovascular and orthopedic writing and have an all-around archived security profile
In this double blind randomized study, a total of 75 corrective spinal surgeries were performed on 75 adolescent patients with idiopathic scoliosis
Patients were randomly allocated in one of three groups (C, HD and LD). Each group included 25 participants. Patients in group C did not receive tranexamic acid and received normal saline. Patients in group HD received tranexamic acid with a loading dose of 50 mg/kg and maintenance dose of 20 mg/kg/h. while patients in group LD received tranexamic acid with a loading dose of 10 mg/kg and maintenance dose of 1 mg/kg/h.

The results showed no significant differences in the hemodynamic parameters between the 3 groups at any of the examined time points.

Similar results were obtained by Goobie et al 11 who found the measured HR, systolic blood pressure, diastolic blood pressure and MAP to be comparable between the two groups when tranexamic acid was used to reduce perioperative blood loss in children undergoing craniosynostosis surgery 
On the contrary, Vel et al 12 found that the mean HR at 4, 6, and 8 h in TXA group was significantly less compared to saline group (P < 0.05). The mean HR (bpm) in immediate postoperative period was 88.06 ± 8.5 and 96.74 ± 8.3 in the saline group (P < 0.001). MAP was higher in the TXA group compared with the saline group. There was a statistically significant difference in MAP between two groups at 4, 6, 8, and 10 h and immediate postoperative period (P < 0.05). They explained this finding by the effect of TXA in decreasing blood loss and thus maintaining better hemodynamics in TXA group 
 
The results of the study showed that there were increased fentanyl consumption in the high dose group (60.5 +/- 12.5ug) more than the low dose group (27 +/- 17.6ug) with a p value <0.001.The control group didn’t receive any added narcotics.

This may be attributed to tranexamic acid as it evoked practices characteristic of unconstrained agony and mechanical allodynia in a focus subordinate way in rats. It directly inhibited GABAA and glycine receptors located at postsynaptic sites in dorsal horn neurons of spinal cord, with increased neuronal excitability. It also blocked the same receptors on excitatory interneurons, which indirectly facilitated stimulatory transmission to the dorsal horn neurons 4
Similar findings were reported in a previous study in which patients who received TXA during the AIS surgery required a higher infusion rate of remifentanil 13
Another study showed that patients who accidentally received intrathecal injections of TXA complained of severe back pain immediately 14-18
Moreover, it has been noticed that patients treated with TXA in the intense period following aneurysmal subarachnoid discharge or hip arthroplasty required higher measurements of analgesics than the dosages required in patients who were not treated with TXA 19, 20
Furthermore, in another study, patients with menorrhagia receiving TXA experienced higher %s of headaches, abdominal pain, and back pain than did the placebo-treated patients 21
In this study, the amount of blood loss decreased by tranexamic acid administration with the least amount in the high dose group (181.25+/-18.7). The low dose group and the control group showed more blood loss (229+/-22.44) and (266.7+/-42.4) respectively.

Similar results were reported in previous studies conducted by Lin et al 22 which showed that High-dose TXA protocol is safe in reducing intraoperative blood loss in adult spinal deformity surgery 
Moreover, Mosaad et al 23 showed that Prophylactic use of large dose of TXA (50 mg/kg loading dose then 20 mg/kg maintenance dose) provided an effective, safe and cheap method for decreasing blood loss during and after spine operations than the use of small dose (10 mg/kg loading dose then 1 mg/kg maintenance dose) 
Furthermore, Kushioka et al 24 showed that High-dose TXA significantly reduced both intra- and postoperative blood loss without causing any complications during or after single-level PLIF 
Also, Ng et al 25 pointed out that patients undergoing posterior spinal corrective surgery with the use of TXA showed much reduced total blood loss, reduced use of transfused blood, much less cell saver blood transfused back to the patient 
Another study done by Vel et al 12 showed that the administration of TXA in a low dose resulted in a significant decline in blood loss associated with better intraoperative hemodynamics 
On the other hand, Elmose et al 26 showed that tranexamic acid does not have a statistically significant effect on intraoperative blood loss. However, they found that the use of TXA can significantly reduce the postoperative blood loss in minor lumbar spine surgery on low risk adult patients 
Results of this study showed shorter surgical duration in the HD group (mean of 128 min; p ; 0.001) compared to the LD and the control group (mean of 188 min versus 208 min respectively)
On the contrary, Elmose et al 26 showed that tranexamic acid does not have a statistically significant effect on operative time
Patients in this study didn’t show any clinical signs of intraoperative or postoperative complications related to the use of tranexamic acid such as deep venous thrombosis
This was similar to Nishihara et al 27 who stated that the utilization of TXA did not seem to affect the prevalence of either proximal DVT or PE after total hip arthroplasty in the absence of routine chemical thromboprophylaxis 
This was in concordance with the meta analysis done by Wei et al 28 which stated that the use of TXA reduced the risk of blood loss and the need for allogeneic blood transfusion significantly, without apparent increased risk of DVT or PE complications 
Absence of DVT detection may be attributed to the short period of the study extending to 24 hours after the operation only. Patients in this study didn’t show any seizures postoperatively associated with the use of tranexamic acid. On the contrary, Schlag et al 29 found that Tranexamic acid retains its convulsive action within Fibrin Sealants. Thus, use of FS containing TXA for surgery within or close to the CNS may pose a substantial risk to the patient 
Also, meta-analysis done by Lin showed that the risk of seizure increased in patients with TXA exposure and the % rate of TXA-associated seizures increased when the dose levels increased. 5 Absence of seizures may be attributed to the anticonvulsant properties of most anesthetics intraoperatively.

TXA has been reported to decrease blood loss in numerous surgeries, however a worry about the ideal dose stays indistinct.

The present study had several limitations. To begin with, the number of studied patients may not reveal all the complications due to their low %. Further studies on a greater scale are needed to unmask them. Second, the effectiveness of tranexamic acid in a population of patients with congenital scoliosis merits consider. Unfortunately, that group is less homogeneous compared to idiopathic scoliosis and differences between treatments groups may be harder to identify. Third, a limitation of this study is that we did not utilize the bispectral index or electroencephalogram to ensure comparable anesthetic depth in all patients because of unavailability of equipment. Lastly, to provide additional information on the efficacy and safety of TXA, multicenter randomized prospective analysis in the future is warranted.

Conclusion:
Despite these previous reports, intraoperative nociception induced by TXA used to reduce intraoperative blood loss was not investigated much. This study demonstrates that intraoperative administration of TXA evokes intraoperative nociception since patients who received TXA required more fentanyl during the AIS surgery.

Conflicts of interest:
There were no conflicts of interest.