Safety and efficacy of aprotinin versus tranexamic acid for reducing absolute blood loss and transfusion in pediatric patients undergoing craniosynostosis surgery: a randomized, double-blind, three-arm controlled trial

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  • 1 Departments of Pediatric Neurosurgery,
  • | 2 Pediatric Anesthesiology, and
  • | 3 Pediatric Intensive Care Medicine, Children’s Medical Center Hospital, Tehran University of Medical Sciences, Tehran, Iran
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OBJECTIVE

Craniosynostosis surgery is associated with considerable blood loss and need for transfusion. Considering the lower estimated blood volume (EBV) of children compared to adults, excessive blood loss may quickly lead to hypovolemic shock. Therefore, reducing blood loss is important in craniosynostosis surgery. This study was conducted to evaluate the efficacy of aprotinin or tranexamic acid (TXA) in blood loss reduction in these patients.

METHODS

In the current randomized controlled trial, 90 eligible pediatric patients with craniosynostosis were randomly divided into three groups to receive either aprotinin, TXA, or no intervention. The absolute blood loss and transfusion amount were assessed for all patients both intraoperatively and 2 and 8 hours postoperatively.

RESULTS

Although crude values of estimated blood loss were not significantly different between groups (p = 0.162), when adjusted to the patient’s weight or EBV, the values reached the significance level (p = 0.018), particularly when the aprotinin group was compared to the control group (p = 0.0154). The EBV losses 2 hours and 8 hours postoperatively significantly dropped in the TXA and aprotinin groups compared to the control group (p = 0.001 and p < 0.001, respectively). Rates of postoperative blood transfusion were significantly higher in the control group (p = 0.024). Hemoglobin and hematocrit 8 hours postoperatively were lower in the control group than in the TXA or aprotinin treatment groups (p < 0.002 and p < 0.001, respectively). There were no serious adverse events associated with the interventions in this study.

CONCLUSIONS

Aprotinin and TXA can reduce blood loss and blood transfusion without serious complications and adverse events in pediatric patients undergoing craniosynostosis surgery.

ABBREVIATIONS

ATN = acute tubular necrosis; CBC = complete blood count; DIC = disseminated intravascular coagulation; EBV = estimated blood volume; FFP = fresh-frozen plasma; Hb = hemoglobin; HCT = hematocrit; INR = international normalized ratio; PRBC = packed red blood cell; PT = prothrombin time; PTT = partial thromboplastin time; rICP = raised intracranial pressure; TXA = tranexamic acid.

OBJECTIVE

Craniosynostosis surgery is associated with considerable blood loss and need for transfusion. Considering the lower estimated blood volume (EBV) of children compared to adults, excessive blood loss may quickly lead to hypovolemic shock. Therefore, reducing blood loss is important in craniosynostosis surgery. This study was conducted to evaluate the efficacy of aprotinin or tranexamic acid (TXA) in blood loss reduction in these patients.

METHODS

In the current randomized controlled trial, 90 eligible pediatric patients with craniosynostosis were randomly divided into three groups to receive either aprotinin, TXA, or no intervention. The absolute blood loss and transfusion amount were assessed for all patients both intraoperatively and 2 and 8 hours postoperatively.

RESULTS

Although crude values of estimated blood loss were not significantly different between groups (p = 0.162), when adjusted to the patient’s weight or EBV, the values reached the significance level (p = 0.018), particularly when the aprotinin group was compared to the control group (p = 0.0154). The EBV losses 2 hours and 8 hours postoperatively significantly dropped in the TXA and aprotinin groups compared to the control group (p = 0.001 and p < 0.001, respectively). Rates of postoperative blood transfusion were significantly higher in the control group (p = 0.024). Hemoglobin and hematocrit 8 hours postoperatively were lower in the control group than in the TXA or aprotinin treatment groups (p < 0.002 and p < 0.001, respectively). There were no serious adverse events associated with the interventions in this study.

CONCLUSIONS

Aprotinin and TXA can reduce blood loss and blood transfusion without serious complications and adverse events in pediatric patients undergoing craniosynostosis surgery.

In Brief

In this study the authors aimed to evaluate the safety and efficacy of tranexamic acid (TXA) versus aprotinin on the rate of blood loss and transfusion within the first 24 hours after craniosynostosis surgery. The adjusted intraoperative blood loss for weight (EBVloss) was lower with aprotinin administration, and both the 2- and 8-hour postoperative EBVloss values were significantly decreased when aprotinin or TXA was administered. These results demonstrated that aprotinin and TXA can reduce blood loss and transfusion without serious adverse events.

Defined as early closure of at least one cranial suture, craniosynostosis results in skull deformity and/or raised intracranial pressure (rICP).1–3 The general occurrence rate is about 4 per 10,000 infants.1,3 Depending on the fused suture, the deformity is termed anterior plagiocephaly with unilateral closure of the coronal suture, brachycephaly with bilateral closure of the coronal suture, scaphocephaly with closure of the sagittal suture, or trigonocephaly with closure of the metopic suture.4,5

Because of the likelihood of rICP and skull deformity, most cases of craniosynostosis require skull reconstruction surgery.6 This procedure is associated with significant blood loss and almost always entails the need for allogeneic blood transfusion of 20% to 500% of the estimated blood volume (EBV).6 Blood transfusion carries potential inherent risks, including viral infection and lung injuries.7 Moreover, massive transfusion and its consequences, especially in pediatric patients whose EBV is lower than that of adults, are other major concerns for the surgical team. Technique modification and less invasive procedures may help reduce bleeding.7 Moreover, a number of pharmacological agents and factors to reduce perioperative blood loss and transfusion have been widely proposed and tested, including recombinant factor VII, fibrinogen, tranexamic acid (TXA; trans-4-aminomethyl cyclohexane carboxylic acid), and aprotinin. Use of recombinant erythropoietin to increase the red cell mass has also been reported.7

In the current investigation, the effects of aprotinin and TXA on absolute blood loss and transfusion were assessed in pediatric patients undergoing craniosynostosis surgery.

Aprotinin, also known as bovine pancreatic trypsin inhibitor (BPTI), is a competitive antagonist of serine proteases such as plasmin, trypsin, and chymotrypsin, which inhibits fibrinolysis. It is used in cardiac and craniofacial surgeries. Testing for allergic responses is recommended before use. Aprotinin is also associated with cardiac, renal, and cerebral complications in patients with atherosclerosis—which is not a problem in our target population.6

TXA is a synthetic analog of lysine used for blood loss as it inhibits the conversion of plasminogen to plasmin by binding at the lysine binding site. TXA is used in surgeries with extensive blood loss, such as cardiac and orthopedic surgeries and, more recently, craniosynostosis surgery.6,8

A randomized, single-center, parallel, double-blind, superiority-controlled trial was conducted to evaluate the safety and efficacy of TXA or aprotinin by assigning 90 craniosynostosis patients into one of three study arms: aprotinin treatment, TXA treatment, or control. The amount of intraoperative and postoperative blood loss and the rate of transfusion within the first 24 hours after surgery were assessed and compared between intervention groups.

Methods

Study Setting and Trial Design

This prospective, double-blind, single-center, three-armed, parallel-controlled, randomized clinical trial study was conducted from 2019 to 2021 in Children’s Medical Center, Tehran, Iran. We enrolled pediatric patients who were candidates for craniosynostosis surgery in this study to assess the effects of interventions for perioperative blood loss and transfusion.

The study was approved and monitored by the ethics committee of the Children’s Medical Center and was registered in the Iranian Registry of Clinical Trials (IRCT; registration no. IRCT20200705048023N1, https://www.irct.ir/). Informed consent was obtained from the parents or legal guardian of each volunteered patient.

Eligibility Criteria

Patients between 2 months and 2 years of age who were candidates for reconstructive surgery for craniosynostosis were screened for eligibility to be included in this study. The inclusion criteria were as follows: 1) single or multisuture craniosynostosis candidates for either canthal advancement or cranial vault remodeling surgery; 2) syndromic or nonsyndromic craniosynostosis; 3) hemoglobin (Hb) level ≥ 13 mg/dl; and 4) signed informed consent provided by the patient’s parents or legal guardian.

Patients were excluded based on the following criteria: 1) indication for endoscopic craniosynostosis surgery; 2) history of coagulopathies or hemoglobinopathies in patient or first-degree relatives (hemophilia, abnormal prothrombin time [PT], partial thromboplastin time [PTT], international normalized ratio [INR], afibrinogenemia, congenital coagulation factor deficiencies); 3) complex craniofacial surgeries; 4) craniosynostosis recurrence; 5) secondary craniosynostosis; 6) abnormal renal function tests, including abnormal blood urea nitrogen and creatinine for age or family history of hereditary renal disease such as polycystic kidney; 7) allergy to aprotinin (tested 30 minutes preoperatively with a testing dose of 1 ml); and 8) congenital heart disease.

Preintervention

Before randomization and intervention all patients were tested for Hb level, and in cases of Hb < 13, transfusion with a maximum dose of 15 ml/kg packed red blood cells (PRBCs) was considered within the last week prior to surgery. The protocol of preoperative transfusion in patients with Hb < 13 has been followed in our ward for more than a decade because most of our patients are malnourished infants with low rates of receiving iron supplements and low levels of serum Hb, necessitating a high volume of PRBC transfusions during surgery. The rationale behind elevating presurgical Hb above this set point was to avoid as much as possible the need for intraoperative massive transfusion in these infants.

Complete blood count (CBC), serum electrolytes, coagulation profile, and renal function tests were assessed as well. Platelets and fresh-frozen plasma (FFP) were transfused, as needed, in accordance with the American Society of Anesthesiologists Task Force on Blood Component Therapy.9

Patient history of iron complement consumption and blood transfusion since birth, and family history of craniosynostosis were recorded for all patients as well. Preoperative cardiac assessments were performed by pediatric cardiologists.

Surgical Procedures

Adequacy of the cardiorespiratory system was assessed prior to anesthesia administration. Patients were given 1 µg/kg fentanyl as the premedication, and anesthesia was induced with 5 mg/kg sodium thiopental and 0.5 mg/kg atracurium. Patients were intubated and mechanical ventilation was adjusted to maintain an arterial partial pressure of carbon dioxide between 30 and 35 mm Hg. Arterial catheters were inserted for invasive blood pressure monitoring. Maintenance of anesthesia was achieved using sevoflurane (end-tidal fraction at 5%) and atracurium.

Surgical approach was chosen based on the type of synostosis. Accordingly, the patients underwent either canthal advancement or vault remodeling (pi procedure). Patients with metopic, unicoronal, or bicoronal craniosynostosis underwent canthal advancement surgery, and those with sagittal or multisuture craniosynostosis underwent vault remodeling surgery.

Interventions

After induction of anesthesia, patients in each treatment group were given a loading dose of the corresponding drug. In the TXA group, TXA was administered at a dose of 50 mg/kg, diluted in normal saline to a volume of 1 ml/kg, and infused within 1 hour with a flow rate of 1 ml/kg/hr.2

In each patient in the aprotinin group, a testing dose of 1 ml (10,000 kallikrein inhibitor units [KIU]) was injected intravenously 30 minutes before induction of anesthesia. In case of no allergic or anaphylactic reaction, aprotinin was loaded with a dose of 35,000 KIU/kg and an infusion rate of 10,000 KIU/kg/hr.

The patients in the control group did not receive either of those drugs or the placebo.

A single anesthesiologist, who was completely blinded to intervention groups, was responsible for estimating intraoperative blood loss. Drug administration was performed by another member of the anesthesiology team who became informed of the intervention groups just before anesthesia.

Outcome Measures

During surgery, the volume of intraoperative blood loss was estimated for each patient. Duration of anesthesia and surgery and urine volumes were recorded. The intraoperative and postoperative blood transfusion volumes and infused perioperative crystalloid serum volumes were also documented. CBC, serum electrolyte, and coagulation profiles were reevaluated after the surgery. Absolute blood loss was calculated postoperatively using the level of postsurgical Hb and hematocrit (HCT).

Primary Outcomes

Operative Blood Loss Measurement

Intraoperative blood loss was measured as the mean of the estimated value by the surgeon and anesthesiologist. Importantly, the intraoperative blood loss was measured as both a crude value and a value adjusted for patient weight and patient EBV. This adjustment was made to compensate for any confounding effects of inter- or intra-arm differences in patient weights.

Absolute estimated blood loss (EBVloss) was calculated through the measurement of Hb and HCT levels 2 and 8 hours postoperatively, considering the patient’s weight, administered fluid volume, and estimated red cell volume loss (ERCVloss), using the following formulas: EBVloss (mg/kg) = ERCVloss (ml)/kg × HCTpreop/100; ERCVloss (ml) = ERCVpreop + ERCVtransfused – ERCVpostop; and ERCVpreop = EBV × HCT/100.

Blood transfusion volumes were measured in milliliters. Intraoperative blood transfusion volume was defined as the volume of intraoperative transfused PRBCs, and postoperative blood transfusion volume was defined as the volume of postoperatively transfused PRBCs.

Intervention-Related Mortality

Investigation of all case mortality resulting from intervention (including anaphylactic shock) was considered the primary objective.

Secondary Outcomes

Secondary outcomes were measured as follows.

The mean difference of the 2- and 8-hour postoperative Hb and HCT values was detected through CBC testing and considered an indirect measurement of postoperative blood loss when the amount of transfused PRBCs was also considered. These values were also used to calculate absolute blood loss.

Duration of anesthesia was defined as the interval between induction of anesthesia and patient awakening, and duration of surgery was defined as the interval between the surgical incision and the last closing suture.

Additional measurements were obtained for the transfused crystalloid and PRBC volume and changes in coagulation test values (PT, PTT, INR).

Calculation of the mortality rate, whether caused by intervention or not, was the secondary objective of the study.

Safety Assessment

To determine the safety of the intervention drugs being tested, all potential adverse reactions in all three groups were recorded and compared with each other (i.e., nausea and vomiting, fever, flu-like symptom, acute tubular necrosis [ATN], disseminated intravascular coagulation [DIC], seizure, and hematuria).

General tolerability of medications was assessed, and all immediate allergic reactions to intervention drugs, including anaphylaxis, were recorded. Study data for patients with immediate adverse reactions were excluded from the final analysis of primary outcomes but were included for assessment of drug tolerability.

Sample Size Calculation

The sample size was calculated based on our primary hypothesis that both aprotinin and TXA reduced blood loss by 20–40 ml/kg compared to control.8,10,11 Based on our calculations, a sample size of 90 was required to achieve an alpha level of 0.01 and a power of 0.95 for this investigation.

Randomization and Concealment

Randomization: The order of study interventions was determined by using a 6-block computer-based randomization master list.

Random allocation: The intervention for each patient was determined according to randomization cards that were ordered according to a randomization master list. A total of 90 patients were randomly divided with a 1:1:1 ratio into TXA, aprotinin, or control groups. The participants were assigned to intervention and control groups by the members of the monitoring board. Group allocation was not influenced by the type of craniosynostosis or type of procedure.

Concealment: The randomization cards were placed in opaque pockets, and for each of the patients one pocket was opened only at the time of random allocation.

Blinding: All participants in the investigation were blinded to patient group allocation, including the anesthesiologist who estimated the amount of blood loss, members of the surgical team, intensive care staff and treating groups, data-collecting persons, patients and their parents, and the data analyzer.

Statistical Analysis

Statistical analysis was performed using IBM SPSS Statistics for Windows version 21 (IBM Corp.). Continuous variables with normal distributions were analyzed using one-way ANOVA, followed by post hoc Tukey analysis for comparison between groups. For non-Gaussian variables, the Kruskal-Wallis test was performed. Categorical variables were analyzed with the chi-square test. A p value < 0.05 was considered statistically significant.

Results

Demographic Characteristics

A total of 90 patients were recruited. Included patients were allocated equally into one of three groups, receiving treatment with aprotinin or TXA in the treatment groups or no treatment in the control group.

The mean age of patients was 10.30 months (range 3–24 months). The male/female ratio was 1.045 (46:44). There were no significant differences between sex, age, weight, rICP, family history of craniosynostosis, history of iron intake, and history of blood transfusion between the three study groups. Detailed demographic characteristics of patients are presented in Table 1.

TABLE 1.

Demographic characteristics of patients in the three intervention groups

Pt GroupTotal (n = 90)p Value
Control (n = 30)TXA (n = 30)Aprotinin (n = 30)
Sex, F/M ratio15:1516:1413:1744:460.733
Age, mos9.31 (5–24)11.43 (4–24)10.16 (5–24)10.30 (3–24)0.132
Weight, kg8.33 (4.6–14) 9.14 (5.2–14) 9.35 (6.2–16.2) 8.94 (4.6–16.2)0.168
Craniosynostosis family history12360.585
rICP signs1179270.530
Prior blood transfusion31040.160
Received iron supplements11611280.274
Mean closed sutures, no.1.761.261.701.570.120
Mean EBV, ml624.75685.75701.75670.750.168

Pt = patient.

Values are presented as mean (range) or number of patients unless otherwise indicated.

rICP was estimated by the operating surgeons, in view of features like splitting of the nonfused sutures or prominent convolutional markings on the inner table of the skull, detected on preoperative 3D skull CT or observed over the bone flaps during surgery.

Frequencies of different types of craniosynostosis (p = 0.412) and types of surgery (p = 0.483) were not significantly different between the three groups, as shown in Table 2.

TABLE 2.

Distribution of craniosynostosis types and surgical approach in the three patient groups

Pt GroupTotal (n = 90)
Control (n = 30)TXA (n = 30)Aprotinin (n = 30)
Craniosynostosis type
 Metopic45817
 Bicoronal3126
 Rt coronal78520
 Lt coronal2619
 Sagittal67720
 Multisuture83718
Op method
 Canthal advancement16201652
 Vault remodeling14101438

Values are numbers of patients.

Preoperative Assessments

There were no significant differences between the study groups in terms of laboratory measurements, number of patients requiring PRBCs, and amount of PRBCs received by each patient. Details on preoperative laboratory results and PRBC transfusion are shown in Table 3.

TABLE 3.

Preoperative laboratory results of patients in the three patient groups

Pt GroupTotal (n = 90)p Value
Control (n = 30)TXA (n = 30)Aprotinin (n = 30)
Received PRBCs preop, no. (%)23 (76.66)21 (70.00)24 (80)68 (75.55)0.656
Mean preop transfused PRBC vol, ml95.6680.6696.0090.770.808
Hb, g/dl14.8514.7214.4214.660.381
HCT, %43.8842.3141.8442.670.088
Platelets, thousands per mm3314,966.67321,033.33324,666.67320,222.220.930
Sodium, mEq/L136.96136.80135.90136.550.259
Potassium, mEq/L4.414.494.484.460.668
PTT, sec33.4333.7332.9633.370.683
PT, sec13.3913.2913.5613.410.254
INR1.061.041.071.060.408

Primary Outcome Measures

The primary outcome measures are shown in Table 4, and more details concerning the primary outcomes are discussed below.

TABLE 4.

Primary outcome measures and monitoring in the three patient groups

Pt GroupTotal (n = 90)p Value
Control (n = 30)TXA (n = 30)Aprotinin (n = 30)
Intraop
 Blood loss, ml70.6665.6662.6666.330.162
 Blood loss, ml/kg8.647.466.887.660.018
 Blood loss/EBV, %11.539.959.1710.210.018
 PRBC transfusion vol, ml77.6673.0071.6674.110.734
 Crystalloid, ml306.16324.66356.33329.050.368
 Blood transfusion, ml/kg9.718.208.028.650.385
Postop
 Received PRBCs, no. (%)10 (33.33)3 (10)3 (10)16 (17.77)0.024
 Mean transfused PRBC vol, ml25.007.007.6613.220.027
 EBVloss, ml/kg
  2 hrs10.306.466.547.770.001
  8 hrs11.777.187.498.81<0.001
  8 − 2 hrs1.470.720.951.040.001

Intraoperative Blood Loss

Results of comparisons of crude values of the estimated blood loss were not significantly different between the three intervention groups (p = 0.162); however, when adjusted to patient weight, the value reached the significance level between groups (p = 0.018). Accordingly, the post hoc Tukey analysis showed that the adjusted intraoperative blood loss was significantly lower in the aprotinin group than in the control group (p = 0.0154), while the difference was not significant in the TXA group (p = 0.1457).

Similarly, when the blood loss was adjusted for EBV, there was a significant difference between the three intervention groups so that the values were lower in the aprotinin and TXA groups than in the control group (p = 0.018).

Absolute Blood Loss

The total EBVloss values at 2 and 8 hours after the operation were calculated as previously described in Methods.

Two hours postoperatively EBVloss dropped from 10.30 ± 6.16 ml/kg in the control group to 6.46 ± 2.82 ml/kg in the TXA group and 6.54 ± 2.93 ml/kg in the aprotinin treatment group (p = 0.001). Post hoc Tukey analysis showed significant differences between the control group and the TXA treatment group (p = 0.002) and the control group and the aprotinin treatment group (p = 0.002), but not between the TXA and aprotinin treatment groups (p = 0.997).

Eight hours postoperatively EBVloss decreased from 11.77 ± 6.74 ml/kg in the control group to 7.18 ± 2.95 ml/kg in the TXA group and 7.49 ± 3.09 ml/kg in the aprotinin treatment group (p < 0.001). Post hoc Tukey analysis yielded results similar to those for EBVloss 2 hours postoperatively (p = 0.001, p = 0.002, and p = 0.964, respectively).

The difference between EBVloss at 8 and 2 hours postoperatively was also higher in the control group than in the TXA and aprotinin treatment groups (1.47 ± 0.95, 0.72 ± 0.84, and 0.95 ± 0.49 ml/kg, respectively; p = 0.001).

Intraoperative Blood Transfusion

Transfused PRBCs and crystalloid volume during surgery were not different between groups, and only 1 patient in the control group received platelets and FFP.

Postoperative Blood Transfusion

Blood transfusion was performed whenever Hb dropped to < 10 g/dl. The number of patients who required PRBC transfusion after surgery was significantly higher in the control group, whereas it was equal in the two intervention groups (p = 0.024). Also, the mean volume of transfused PRBCs was higher in the control group (p = 0.027).

Intervention-Related Mortality

There were no cases of mortality associated with the interventions in this study.

Secondary Outcome Measures

The secondary outcome measures are shown in Table 5, and further details are described below.

TABLE 5.

Secondary outcome measures and monitoring in the three patient groups

Pt GroupTotal (n = 90)p Value
Control (n = 30)TXA (n = 30)Aprotinin (n = 30)
Intraop
 Anesthesia duration, mins126.50141.33138.33135.380.243
 Op duration, mins93.16102.5095.6697.110.315
 Urine vol, ml73.66102.1696.0090.440.119
 Received platelets, no. of pts10010.364
 Received FFP, no. of pts10010.364
Postop
 Hb 2 hrs postop, g/dl13.1513.5913.7913.510.284
 HCT 2 hrs postop, %38.3739.9340.5739.620.117
 Hb 8 hrs postop, g/dl11.6212.9312.7512.430.002
 HCT 8 hrs postop, %33.9637.6437.5636.390.001
 Sodium, mEq/L136.90136.13136.93136.650.616
 Potassium, mEq/L4.464.284.204.310.080
 PTT, sec33.7333.1334.0033.620.366
 PT, sec14.9314.3614.7814.690.313
 INR1.2461.2481.2431.2460.996
 Received FFP, no. of pts557170.748
 Received platelets, no. of pts00110.364
 Received vitamin K, no. of pts535130.698

Regarding the duration of anesthesia and surgery, neither TXA nor aprotinin decreased the operation and anesthesia time (p = 0.315 and p = 0.243, respectively).

According to analyses of mean differences of 2- and 8-hour postoperative Hb and HCT values, the 2-hour postsurgery Hb and HCT values did not differ among groups, whereas the 8-hour postoperative Hb and HCT levels were statistically lower in controls than in patients treated with TXA or aprotinin. The estimated marginal mean values of Hb and HCT over time showed a significant decline in the control group compared to both the TXA and aprotinin treatment groups (p < 0.002 and p < 0.001, respectively).

Changes in measurement results for coagulation test (PT, PTT, INR) and electrolyte values were not different between the three patient groups. With regard to the all-case mortality rate, all of the patients in this study were alive after surgery and had an uneventful postoperative period. No mortalities were reported in any of the three groups.

Safety Assessments

Adverse Reactions

There were no serious adverse events associated with the interventions either during or after surgery, except for an episode of seizure in 1 patient in the TXA group. Even though 1 patient in each group developed postoperative hematuria, none of these events were cases of DIC or other serious coagulopathy, and all were successfully managed. Other complications and their frequencies are mentioned in Table 6.

TABLE 6.

Safety assessment and adverse events

Pt GroupTotal (n = 90)p Value
Control (n = 30)TXA (n = 30)Aprotinin (n = 30)
Anaphylaxis0000NS
Seizure0101NS
Electrolyte disturbance0000NS
ATN0000NS
Hematuria1113NS
Fever1214NS
Flu-like symptoms0101NS
Nausea/vomiting0011NS
DIC0000NS
Death 0000NS

NS = not significant.

Values are numbers of patients.

General Tolerability of Drugs

All of the patients in the aprotinin group were tested for allergic reactions, and all 30 patients tolerated the medicine without any adverse reactions. Generally, both of the intervention drugs in this study, aprotinin and TXA, were well tolerated in the studied patients.

Discussion

The current randomized controlled trial was conducted to determine and compare the efficacies of aprotinin and TXA in blood loss reduction during and after craniosynostosis surgery. Accordingly, the adjusted intraoperative blood loss by patient weight or EBV was significantly lower when aprotinin was administered to the patient. Moreover, the EBVloss values both 2 and 8 hours postoperatively were significantly decreased when aprotinin or TXA was administered. The respective postoperative transfusion rates and decreases of Hb and HCT levels were lower in the TXA and aprotinin groups than in the control group.

Blood Loss and Major Surgeries

Blood loss is the main concern regarding any major surgery, particularly in pediatric patients due to their low blood volume. Time-consuming surgeries predispose patients to massive blood loss in complicated and major operations. Massive blood loss may lead to serious conditions such as hypovolemic shock, coagulopathy, and organ failure. Different methods have been suggested to prevent these complications, such as elective transfusion of blood products. Nevertheless, massive blood transfusion is frequently accompanied by a series of serious complications, such as coagulopathy, transfusion-related acute lung injury (TRALI), acid-base and electrolyte disturbances, and infection.9 Regarding these issues, in the current study, both TXA and aprotinin were found to be efficient in controlling intraoperative and postoperative blood loss and reducing the need for transfusions of blood products.

Effect of TXA on Blood Loss and Transfusion in Craniosynostosis Surgeries

TXA, a glycoprotein IIb–IIIa inhibitor, inhibits plasmin-mediated lysis of fibrin clots. Some of its rare adverse effects are thrombosis, anaphylaxis, seizure, nausea, and vomiting. TXA is used for orthopedic, cardiac, and dental operations in patients with hemophilia.6,8

A previously reported comparison of TXA treatment with placebo in pediatric craniosynostosis surgery revealed reduced intraoperative and postoperative blood loss and decreased blood and FFP transfusion during surgery, while unlike the present study, postoperative red blood cell transfusion was not decreased significantly.10 On the other hand, a similar study revealed that administration of TXA for craniosynostosis surgery resulted in significant reduction in the volume of transfused packed erythrocytes by 85% intraoperatively and by 57% during the study follow-up period (p < 0.05). Meanwhile, patients in the TXA group were less likely to need intraoperative blood transfusion than were controls (p < 0.05).6 Another study on the same surgical procedure demonstrated that administration of TXA remarkably decreased the estimated blood loss for patients with minimally invasive surgery (p = 0.0231). Although the transfusion volume was lower in the TXA group, the median transfusion volume difference was not significant between groups (p = 0.0723).12 Similarly, Song et al. reported in 2013 that administration of TXA significantly reduced transfusion of PRBCs (p < 0.00001).13 A meta-analysis on 4 studies showed that the difference was statistically significant (p = 0.0006) between the TXA groups and the control groups. However, the subgroup analysis on randomized controlled trials showed that patients in the TXA group did not have significantly reduced blood loss during surgery compared with patients in the placebo group (p = 0.14).7

In the current study, only 10% of patients in the TXA group received PRBCs after the operation, a rate that was lower than the rate observed in a previous study by Ongun et al. (23.5%)14 and higher than the rate reported in a study by Goobie et al. (0%).8 The postoperative EBVloss after 8 hours was significantly lower in the TXA group than in the control group, as similarly shown by Goobie et al. (median 3 ml/kg vs 12 ml/kg);8 however, the difference was not significant in other previous studies.6,14

While a previous study by Goobie et al. on TXA at a dose of 50 mg/kg demonstrated a significant effect on reducing perioperative blood loss and blood transfusion,8 their recent study comparing low-dose (10 mg/kg) with high-dose (50 mg/kg) TXA administration in craniosynostosis surgery showed that high doses of TXA did not have advantages over low doses in decreasing intraoperative blood loss and blood transfusion.15 The use of TXA in combination with other techniques for reducing blood loss and blood transfusion also showed successful results in previous studies.16,17 In concordance with the mentioned studies, the current study showed efficacy of TXA on EBVloss both 2 hours and 8 hours postoperatively and on the rate of postoperative transfusion. Contrary to the results of the current study and previously reported research,6,8 one meta-analysis on TXA in craniosynostosis surgery showed that increased use of TXA over a period of years increased blood transfusion and complication rates.18

Effect of Aprotinin on Blood Loss and Transfusion in Craniosynostosis Surgeries

Aprotinin is an antifibrinolytic drug that is commonly used in many types of surgery. A competitive serine protease inhibitor, aprotinin is also used for its anti-inflammatory effects and postoperative blood loss prevention in some orthopedic and cardiac surgeries. Anaphylaxis, acute renal failure, heart failure, and encephalopathy are known to be rare side effects of aprotinin.6

Studies on the efficacy of aprotinin in craniosynostosis remodeling surgery have been limited, and only a scant number of published studies are available. Gunnarsson et al. compared an aprotinin-treated group of patients with a control group undergoing craniosynostosis surgery. The median values of blood loss and requirement for blood transfusion during the operation decreased from 22% to 3.9% and 21.1% to 0%, respectively, in the treatment group compared with the control group (p < 0.001).7 While a similar study had shown that estimated blood loss was not significantly lower in the aprotinin group, this study also showed that the intraoperative and first 3-day postoperative rates of blood transfusion were significantly lower in the aprotinin group (32 vs 52 and 33 vs 57 ml/kg, respectively, p = 0.03).11 According to Ahmed et al. in 2014, administration of aprotinin for pediatric craniofacial surgeries resulted in significantly less colloid administration and blood transfusion in the aprotinin-treated group (p < 0.003). Aprotinin was associated with decreased PRBC transfusion requirements in children undergoing craniofacial surgery.19 In concordance with previous studies, the current study showed that administration of aprotinin significantly decreased the adjusted intraoperative blood loss according to weight or EBV, both 2 hours and 8 hours postoperation.

Effect of TXA and Aprotinin on Delayed Blood Loss

According to the results of this trial, the 2-hour postsurgery Hb and HCT values did not differ among groups, while the 8-hour postoperative Hb and HCT values were statistically lower in control patients compared to patients treated with TXA or aprotinin. From this finding it can be inferred that the antifibrinolytic effect of these agents could decrease postoperative blood oozing and reduce delayed postoperative blood loss. Longer postoperative follow-up of Hb and HCT levels is needed to better assess the plausibility of this hypothesis.

Safety Issues Regarding Complications and Thrombotic Events

In the current study, the coagulation tests were not different among the study groups, while INR and PT were significantly increased after surgery in all groups. These results may have been due to factor VII consumption. No serious coagulopathy complications were observed in any of the patient groups.

Thrombotic events did not occur in any groups, unlike previous studies.20 There were no occurrences of allergic reactions, renal failure, or cardiac complications, and other serious complications and death were not reported.

Study Limitations and Further Directions

Although efforts were made to eliminate the sources of bias and overcome the study limitations, the current study was designed based on standard doses of aprotinin and TXA. Since some medications may have dose-dependent effects, the influence of different doses could be evaluated as well. Moreover, longer postoperative follow-up could lead to better estimation of postsurgical blood loss and adverse events. Therefore, further studies with different doses of each agent and a longer postoperative follow-up period may be of help.

Conclusions

The results of the current study demonstrated that TXA and aprotinin can reduce blood loss and blood transfusion without serious complications and adverse events in pediatric craniosynostosis remodeling surgery. The aprotinin group had a significantly lower percentage of blood loss than the controls during the operation, while the percentage of blood loss difference was not significant between TXA and the control group. Except for the percentage of intraoperative blood loss, aprotinin showed no superiority over TXA in this study.

Disclosures

The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

Author Contributions

Conception and design: Habibi, Hanaei. Acquisition of data: Dabbagh Ohadi, Khademi. Analysis and interpretation of data: Habibi, A Ebrahim Soltani. Drafting the article: Z Ebrahim Soltani, Maroufi. Critically revising the article: Hanaei, Tayebi Meybodi. Reviewed submitted version of manuscript: Nejat. Approved the final version of the manuscript on behalf of all authors: Habibi. Statistical analysis: Z Ebrahim Soltani. Administrative/technical/material support: Yaghmaie, A Ebrahim Soltani, Nejat. Study supervision: Habibi.

References

  • 1

    French LR, Jackson IT, Melton LJ III. A population-based study of craniosynostosis. J Clin Epidemiol. 1990;43(1):6973.

  • 2

    Vega RA, Lyon C, Kierce JF, Tye GW, Ritter AM, Rhodes JL. Minimizing transfusion requirements for children undergoing craniosynostosis repair: the CHoR protocol. J Neurosurg Pediatr. 2014;14(2):190195.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 3

    White N, Bayliss S, Moore D. Systematic review of interventions for minimizing perioperative blood transfusion for surgery for craniosynostosis. J Craniofac Surg. 2015;26(1):2636.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4

    Persing J, James H, Swanson J, Kattwinkel J. Prevention and management of positional skull deformities in infants. American Academy of Pediatrics Committee on Practice and Ambulatory Medicine, Section on Plastic Surgery and Section on Neurological Surgery. Pediatrics.2003;112(1 Pt 1):199202.

    • Search Google Scholar
    • Export Citation
  • 5

    Kolar JC. An epidemiological study of nonsyndromal craniosynostoses. J Craniofac Surg. 2011;22(1):4749.

  • 6

    Dadure C, Sauter M, Bringuier S, et al. Intraoperative tranexamic acid reduces blood transfusion in children undergoing craniosynostosis surgery: a randomized double-blind study. Anesthesiology. 2011;114(4):856861.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7

    Gunnarsson I, Hlynsson , Rosmundsson T, Thorsteinsson A. Haemostatic effect of aprotinin during craniosynostotic surgery in children. Acta Anaesthesiol Scand. 2011;55(8):10101014.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8

    Goobie SM, Meier PM, Pereira LM, et al. Efficacy of tranexamic acid in pediatric craniosynostosis surgery: a double-blind, placebo-controlled trial. Anesthesiology. 2011;114(4):862871.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9

    Sihler KC, Napolitano LM. Complications of massive transfusion. Chest. 2010;137(1):209220.

  • 10

    Fenger-Eriksen C, D’Amore Lindholm A, Nørholt SE, et al. Reduced perioperative blood loss in children undergoing craniosynostosis surgery using prolonged tranexamic acid infusion: a randomised trial. Br J Anaesth. 2019;122(6):760766.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11

    D’Errico CC, Munro HM, Buchman SR, Wagner D, Muraszko KM. Efficacy of aprotinin in children undergoing craniofacial surgery. J Neurosurg. 2003;99(2):287290.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12

    Maugans TA, Martin D, Taylor J, Salisbury S, Istaphanous G. Comparative analysis of tranexamic acid use in minimally invasive versus open craniosynostosis procedures. J Craniofac Surg. 2011;22(5):17721778.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13

    Song G, Yang P, Zhu S, et al. Tranexamic acid reducing blood transfusion in children undergoing craniosynostosis surgery. J Craniofac Surg. 2013;24(1):299303.

  • 14

    Ongun EA, Dursun O, Kazan MS. Tranexamic acid utilization in craniosynostosis surgery. Turk Neurosurg. 2020;30(3):407415.

  • 15

    Goobie SM, Staffa SJ, Meara JG, et al. High-dose versus low-dose tranexamic acid for paediatric craniosynostosis surgery: a double-blind randomised controlled non-inferiority trial. Br J Anaesth. 2020;125(3):336345.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16

    Wood RJ, Stewart CN, Liljeberg K, Sylvanus TS, Lim PK. Transfusion-free cranial vault remodeling: a novel, multifaceted approach. Plast Reconstr Surg. 2020;145(1):167174.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17

    Escher PJ, Tu AD, Kearney SL, et al. A protocol of situation-dependent transfusion, erythropoietin and tranexamic acid reduces transfusion in fronto-orbital advancement for metopic and coronal craniosynostosis. Childs Nerv Syst. 2021;37(1):269276.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18

    Danforth RM, Cook JA, Bennett WE, Tholpady SS, Gerety PA. Tranexamic acid in infantile craniosynostosis surgery: friend or foe? Plast Reconstr Surg. 2020;146(5):11191127.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 19

    Ahmed Z, Stricker L, Rozzelle A, Zestos M. Aprotinin and transfusion requirements in pediatric craniofacial surgery. Paediatr Anaesth. 2014;24(2):141145.

  • 20

    Roumeliotis G, Campbell S, Das S, et al. Central retinal artery occlusion following prone transcranial surgery for craniosynostosis and discussion of risk factors. J Craniofac Surg. 2020;31(6):15971601.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

Diagram from Behbahani et al. (pp 488–496).

  • 1

    French LR, Jackson IT, Melton LJ III. A population-based study of craniosynostosis. J Clin Epidemiol. 1990;43(1):6973.

  • 2

    Vega RA, Lyon C, Kierce JF, Tye GW, Ritter AM, Rhodes JL. Minimizing transfusion requirements for children undergoing craniosynostosis repair: the CHoR protocol. J Neurosurg Pediatr. 2014;14(2):190195.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 3

    White N, Bayliss S, Moore D. Systematic review of interventions for minimizing perioperative blood transfusion for surgery for craniosynostosis. J Craniofac Surg. 2015;26(1):2636.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4

    Persing J, James H, Swanson J, Kattwinkel J. Prevention and management of positional skull deformities in infants. American Academy of Pediatrics Committee on Practice and Ambulatory Medicine, Section on Plastic Surgery and Section on Neurological Surgery. Pediatrics.2003;112(1 Pt 1):199202.

    • Search Google Scholar
    • Export Citation
  • 5

    Kolar JC. An epidemiological study of nonsyndromal craniosynostoses. J Craniofac Surg. 2011;22(1):4749.

  • 6

    Dadure C, Sauter M, Bringuier S, et al. Intraoperative tranexamic acid reduces blood transfusion in children undergoing craniosynostosis surgery: a randomized double-blind study. Anesthesiology. 2011;114(4):856861.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7

    Gunnarsson I, Hlynsson , Rosmundsson T, Thorsteinsson A. Haemostatic effect of aprotinin during craniosynostotic surgery in children. Acta Anaesthesiol Scand. 2011;55(8):10101014.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8

    Goobie SM, Meier PM, Pereira LM, et al. Efficacy of tranexamic acid in pediatric craniosynostosis surgery: a double-blind, placebo-controlled trial. Anesthesiology. 2011;114(4):862871.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9

    Sihler KC, Napolitano LM. Complications of massive transfusion. Chest. 2010;137(1):209220.

  • 10

    Fenger-Eriksen C, D’Amore Lindholm A, Nørholt SE, et al. Reduced perioperative blood loss in children undergoing craniosynostosis surgery using prolonged tranexamic acid infusion: a randomised trial. Br J Anaesth. 2019;122(6):760766.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11

    D’Errico CC, Munro HM, Buchman SR, Wagner D, Muraszko KM. Efficacy of aprotinin in children undergoing craniofacial surgery. J Neurosurg. 2003;99(2):287290.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12

    Maugans TA, Martin D, Taylor J, Salisbury S, Istaphanous G. Comparative analysis of tranexamic acid use in minimally invasive versus open craniosynostosis procedures. J Craniofac Surg. 2011;22(5):17721778.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13

    Song G, Yang P, Zhu S, et al. Tranexamic acid reducing blood transfusion in children undergoing craniosynostosis surgery. J Craniofac Surg. 2013;24(1):299303.

  • 14

    Ongun EA, Dursun O, Kazan MS. Tranexamic acid utilization in craniosynostosis surgery. Turk Neurosurg. 2020;30(3):407415.

  • 15

    Goobie SM, Staffa SJ, Meara JG, et al. High-dose versus low-dose tranexamic acid for paediatric craniosynostosis surgery: a double-blind randomised controlled non-inferiority trial. Br J Anaesth. 2020;125(3):336345.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16

    Wood RJ, Stewart CN, Liljeberg K, Sylvanus TS, Lim PK. Transfusion-free cranial vault remodeling: a novel, multifaceted approach. Plast Reconstr Surg. 2020;145(1):167174.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17

    Escher PJ, Tu AD, Kearney SL, et al. A protocol of situation-dependent transfusion, erythropoietin and tranexamic acid reduces transfusion in fronto-orbital advancement for metopic and coronal craniosynostosis. Childs Nerv Syst. 2021;37(1):269276.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18

    Danforth RM, Cook JA, Bennett WE, Tholpady SS, Gerety PA. Tranexamic acid in infantile craniosynostosis surgery: friend or foe? Plast Reconstr Surg. 2020;146(5):11191127.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 19

    Ahmed Z, Stricker L, Rozzelle A, Zestos M. Aprotinin and transfusion requirements in pediatric craniofacial surgery. Paediatr Anaesth. 2014;24(2):141145.

  • 20

    Roumeliotis G, Campbell S, Das S, et al. Central retinal artery occlusion following prone transcranial surgery for craniosynostosis and discussion of risk factors. J Craniofac Surg. 2020;31(6):15971601.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

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