Pediatric Anesthesia ISSN 1155-5645
ORIGINAL ARTICLE
Prophylactic versus reactive transfusion of thawed plasma in patients undergoing surgical repair of craniosynostosis: a randomized clinical trial Benjamin J. Pieters1, Lisa Conley1, Jennifer Weiford1, Marilyn Hamilton2, Brian Wicklund3, Adam Booser1, Adam Striker1, Susan Whitney1 & Virender Singhal4 1 2 3 4
Department of Anesthesiology, Children’s Mercy Hospital and Clinics, Kansas City, MO, USA Department of Pathology, Children’s Mercy Hospital and Clinics, Kansas City, MO, USA Department of Hematology-Oncology, Children’s Mercy Hospital and Clinics, Kansas City, MO, USA Department of Plastic Surgery, Children’s Mercy Hospital and Clinics, Kansas City, MO, USA
What is known
• Craniosynostosis repair in young children is associated with copious bleeding. • A dilutional coagulopathy is frequently observed requiring replacement of clotting factors with plasma. What this article adds
• Prophylactic plasma administration significantly increased the use of plasma and improved coagulation values but did not change blood loss or red cell transfusion requirements.
Implications for translation
• Timely transfusion of plasma according to current practice guidelines is adequate for hemostasis.
Keywords pediatrics; blood loss; craniosynostosis; blood component transfusion; fresh frozen plasma; blood volume Correspondence Dr. Benjamin J. Pieters, Department of Anesthesiology, Children’s Mercy Hospital and Clinics, 2401 Gillham Rd., Kansas City, 64108 Missouri, USA Email: [email protected] Section Editor: Andrew Davidson Accepted 21 October 2014 doi:10.1111/pan.12571
© 2014 John Wiley & Sons Ltd Pediatric Anesthesia 25 (2015) 279–287
Summary Background: Surgical repair of craniosynostosis in young children is associated with copious bleeding and often coagulopathy. Typically, a reactive transfusion strategy is used to treat coagulopathy whereby fresh frozen plasma (FFP) is given only after clinical manifestation of clotting abnormality. This prospective, randomized clinical trial was designed to test the hypothesis that prophylactic FFP during craniofacial surgery reduces blood loss and blood transfusion requirements compared to a reactive FFP transfusion strategy. Methods: Eighty-one patients less than 2 years of age requiring primary repair of craniosynostosis were randomized to receive FFP using either a prophylactic or reactive strategy. Laboratory values were measured at four standardized time points. The volume of blood products transfused, length of stay in the pediatric intensive care unit (PICU), hospital length of stay, and number of donor exposures were recorded for each patient. Results: The prophylactic FFP group received a significantly greater average volume of FFP compared to the reactive group (29.7 mlkg1 vs 16.1 mlkg1; P < 0.001), which was associated with improvement in coagulation values at multiple time points. However, there was no difference in blood transfusion requirements or blood loss between the two groups. The two transfusion strategies resulted in similar median donor exposures. There was no difference in PICU or hospital length of stay.
279
B. J. Pieters et al.
FFP during craniofacial surgery
Conclusion: A reactive FFP transfusion strategy required less plasma transfusion and was associated with similar rates of blood loss and PRBC transfusion as prophylactic FFP despite improvement in coagulation values in the prophylactic FFP group.
Introduction
Methods
The invasiveness of modern craniofacial surgery combined with the physiologic characteristics of younger children, notably a large head:body ratio and small blood volume, conspires to produce significant operative hemorrhage. Indeed, bleeding is the primary cause of morbidity and mortality associated with major craniofacial surgery (1). Predictable intraoperative periods, such as incising the scalp and elevation of bone flaps, are frequently associated with rapid blood loss requiring vigorous transfusion. Several blood conservation techniques have been used in an attempt to attenuate the often massive need for blood products in craniofacial surgery (2–8). However, the specific management of blood products in the OR remains debated in the literature and in clinical practice (9–11). Traditionally, plasma-poor packed red blood cells (PRBCs) are used for blood replacement. The use of such plasma-poor packed red cells can lead to clotting factor dilution, especially when given in the large volumes required for craniofacial surgery (12–16). Thus, clotting factor replacement, typically with fresh frozen plasma (FFP), is frequently necessary during craniofacial surgery and is usually given in a reactive manner once coagulation values have become abnormal. Given that blood loss averages close to one blood volume (17– 19), variability in bleeding is high, and it is difficult to predict outliers, it may be reasonable to give FFP routinely. Some authors advocate for the use of prophylactic FFP on the basis of improvement in postoperative coagulation values and improvement in clinical outcomes (10,13,20). Unfortunately, these recommendations are based on retrospective data. To test the efficacy of prophylactic FFP in the craniofacial surgical population, we have designed a prospective, randomized clinical trial comparing a traditional reactive FFP transfusion strategy (i.e., when laboratory and clinically defined coagulopathy is present) with prophylactic FFP transfusion. We hypothesized that administration of prophylactic FFP improves hemostasis and thereby decreases blood loss and red cell transfusion needs in children undergoing correction of craniosynostosis. Secondary outcomes include coagulation and arterial blood gas laboratory parameters, number of donor exposures, and pediatric intensive care unit (PICU) and hospital length of stay.
Approval for the study was obtained from the IRB at Children’s Mercy Hospital. Written informed consent was obtained from the legal guardian of 81 patients scheduled to undergo primary repair for craniosynostosis with either frontal orbital advancement (FOA) and/ or total calvarial reshaping and expansion (TCRE). Children were excluded for repeat craniofacial surgery, if they were older than 2 years at the time of surgery or if there was a history of complex congenital heart disease, coagulopathy, and liver or kidney disease. Craniosynostosis considered secondary to a syndrome was initially an exclusion criterion but later was removed with IRB approval in an attempt to improve the pace of accruement. The trial was not registered prior to patient enrollment because preenrollment registration was not required at the time the trial started. Red cell and hemostatic blood product transfusion was per protocol as was volume resuscitation. Briefly, when red cell transfusion was indicated, either by the blood product transfusion protocol (Table 1) or by the volume resuscitation protocol (Figure 1), the prophylactic group received PRBCs and FFP in equal volumes (10 mlkg1 each product) to ensure an adequate volume of each blood product to be clinically meaningful in a 1 : 1 PRBC : FFP ratio. The reactive transfusion group received PRBC (10 mlkg1) only, when blood transfusion was indicated. As volume status dictated additional boluses of colloid as specified in Figure 1, both groups were balanced in terms of colloid administration for the intraoperative period. Consistent with common clinical practice, 15 mlkg1 of FFP was transfused if criteria in Table 1 were met. Both the surgeon and the anesthesia team had to agree to give FFP if the decision was based only on the clinical criteria in Table 1. Given that PRBC units usually have a larger volume than FFP units, it was allowable to give the last part of a PRBC unit (≤50 ml) without FFP in the prophylactic group in order to minimize FFP waste. Factor VIIa was included in the study protocol as a rescue agent because of a recommendation by the hematology department at our institution. Cryoprecipitate was not part of the intraoperative study protocol. We used a single-donor program that has previously been described at out institution (21) whereby units of PRBC and FFP can be obtained from the same donor.
280
© 2014 John Wiley & Sons Ltd Pediatric Anesthesia 25 (2015) 279–287
B. J. Pieters et al.
Table 1 Volume resuscitation protocol 1. PRBC transfusion criteria: a. Hb 27 do not transfuse PRBC 2. FFP transfusion criteria: a. Signs and symptoms of coagulopathy/microvascular bleeding and (time permitting): b. PT > 18 s or PTT > 43 s or fibrinogen < 100 then transfuse FFP 15 mlkg1 3. Platelets transfusion criterion: a. Platelet count 35.5°C. Standard ASA monitors were used as well as an arterial blood pressure catheter and a urinary catheter in all cases and a central venous catheter at the discretion of the anesthesiologist. Anesthesia was maintained with isoflurane (endtidal minimum alveolar concentration = 0.75–1.5) in an oxygen and air mixture, remifentanil infusion 0.1– 0.5 mcgkg1h1, and rocuronium. Patients were mechanically ventilated to maintain normocapnia. Surgical correction consisted of frontal orbital advancement, total calvarial reshaping and expansion, or both. Epinephine 1 : 100 000 was injected by the surgeon prior to surgical incision. All procedures were performed by the same surgeon. Preoperative fluid deficit was calculated as maintenance fluid (4, 2, 1 method) multiplied by the number of hours nil per os. Deficit volume was replaced with lactated ringers: half of the deficit in the first hour of surgery and one-fourth of the deficit for each of the next 2 h. Maintenance fluid was provided as an infusion of Plasma-Lyte 148 at the rate calculated above during the entire surgical procedure. Thawed plasma was brought to the OR along with the first unit of PRBC in both groups and was suspended from an IV pole after being placed in an opaque plastic bag to blind the surgeon to group allocation and thus reduce requests for FFP transfusion based on clinical criteria alone, for example, microvascular bleeding on the field. Intraoperatively, arterial blood gas measurement was obtained at least hourly and more often at the discretion of the anesthesiologist. A CBC and coagulation panel (protime, partial thromboplastin time, and fibrinogen) were obtained at four standardized times for each patient: approximately 2 weeks prior to surgery (T1), intraoperatively after all skull bone removal (T2), immediately postoperatively (T3), and six hours postoperatively (T4). Goal Hct for the end of the surgery was 28%. At the end of surgery, patients were taken to the postanesthesia care unit (PACU) and extubated awake. After initial stabilization in the PACU, patients were transferred to the pediatric intensive care unit (PICU) for overnight observation, as per standard care at our institution. Treatment of coagulation parameters and blood transfusion while the patient was in the pediatric intensive care unit (PICU) were not strictly protocolized, rather it was recommended that transfusion of blood occurs for hematocrit 18 or PTT >43. Cryoprecipitate was not part of the study 281
B. J. Pieters et al.
FFP during craniofacial surgery
protocol and its use, as well as transfusion of all blood products while the patient remained in the PICU, was ultimately up to the discretion of the PICU team, who were not blinded to group allocation. The triggering hematocrit immediately prior to transfusion in the PICU was recorded to allow comparison between groups. Blood loss was calculated as previously described for craniosynostosis repair (6,16,22) according to the formula: ERCVlost ¼ ERCVpreop þ ERCVtransfused ERCVpostop Where ERCV (estimated red cell volume) = Estimated blood volume 9 hematocrit/100. A value of 80 mlkg1 was used for estimated blood volume for all patients. ERCVtransfused = 0.66 9 PRBC transfused (ml) intraoperatively as the average hematocrit of PRBC units at our institution is 66%. Parametric and nonparametric data were presented as mean and standard deviation or median and range, respectively. Differences were calculated using two-sided t-test for parametric data or Wilcoxon rank sum for nonparametric data. Categorical data were compared using Fisher’s exact or chi-square test as appropriate and are represented as frequency and percent. Additionally, absolute difference in mean or odds ratio and corresponding 95% confidence intervals were calculated, if possible, for continuous and binary variables, respectively. Power analysis was undertaken with the assumption that a 25% reduction in blood transfusion would be clinically significant. Two-sided a was assigned at P < 0.05 as the criterion for statistical significance. With 40 patients per group, there would be 80% power to detect a significant difference between groups. Statistical analyses were performed using SAS software version 9.2 (SAS, Cary, NC, USA). Results A total of 81 patients ranging in age from 6 to 23 months were prospectively enrolled between July 2007 and September 2012. All patients were randomized to either the treatment group (N = 41) or the control group (N = 40). Two patients, one in the control group and one in the treatment group, experienced extreme hemodynamic instability intraoperatively resulting in the anesthesia provider being unable to comply with the study protocol. Two analyses were performed: a per-protocol analysis excluding the two protocol violation patients, and an intention to treat analysis including all patients. The results did not change significantly by type of analysis, and for the 282
sake of concision, the results are reported for the per-protocol analysis only with the exception of our primary outcome variable transfusion of PRBC, for which both data sets are reported. Groups were similar with respect to demographic and surgical characteristics (Table 2). As shown in Table 3, the two groups received virtually identical volumes of crystalloid and there was no significant difference in volume of total nonred cell colloid (albumin + FFP) administered in the operative period. However, the relative distribution of type of colloid differed with greater albumin and less FFP in the reactive group and the opposite trend in the treatment group (Tables 3 and 4). In fact, the prophylactic strategy resulted in significantly more FFP transfusion, both in terms of percent of patients receiving FFP (100% vs 74%; P = 0.003) and mean volume of FFP given per group (29.7 mlkg1 vs 16.1 mlkg1; P < 0.001). The prophylactic group did not require any additional administration of FFP beyond that given with PRBCs, that is, the study intervention. The reactive group received FFP in 15 mlkg1 boluses as per Table 1 criteria with two patients (5%) requiring transfusions based only on clinical criteria and the remainder according to both clinical and laboratory criteria. All patients received PRBCs perioperatively. Hematocrit levels measured at standardized time points designated T1–T4 are presented in Table 5 and showed no significant difference between groups, indicating compliance with a strict red cell transfusion protocol. Perioperative blood product totals are summarized in Table 4. The two groups did not differ significantly in PRBC transfusion or estimated red cell volume loss. There were 17 patients in the reactive transfusion group who required PRBC postoperatively with average measured postoperative Hct prior to transfusion of 23.1%, while 20 patients in the prophylactic group received PRBC postoperatively with pretransfusing Hct of 22.8% (P = 0.78). In the PICU, cryoprecipitate was given to four of the reactive group patients and none of
Table 2 Baseline demographics
Age (months) Weight (kg) Gender (M/F) Syndrome present Y/N FOA/TCRE/Both Length of surgery (min)
Prophylactic Group (N = 40)
Reactive Group (N = 39)
12.1 3.9 9.9 1.8 24/16 1/39 16/22/2 234 29.8
11 2.7 9.3 1.4 19/20 3/36 10/29/0 225 26.4
FOA, Frontal orbital advancement; TCRE, Total calvarial reshaping and expansion. © 2014 John Wiley & Sons Ltd Pediatric Anesthesia 25 (2015) 279–287
B. J. Pieters et al.
FFP during craniofacial surgery
Table 3 Intraoperative fluid and metabolic parameters Fluid parameter
Prophylactic Group (N = 40)
Blood volume lost (%) Crystalloid (mlkg1) Albumin 5% (mlkg1) Total Colloid (mlkg1)a Urine output (mlkg1h1)
102 57.2 17.1 80 2.3
Metabolic parameter 1
Ca < 1 mmoll BE ≤ 6 mmoll1 Metabolic acidosisb Sodium ≤130 mmoll1 ++
45.4 13.4 14.2 37.4 1.6
Reactive Group (N = 39) 95.8 57.7 28.6 77 2
51 13.7 16.5 45.9 1.7
Difference in mean (95% CI)
P value
19.56 (103.6, 64.47) 0.48 (5.59, 6.55) 11.54 (4.65, 18.43) 2.98 (21.7, 15.74) 0.23 (0.96, 0.51)
0.57 0.88 0.001* 0.66 0.54
n (%)
n (%)
Odds ratio (95% CI)
P value
12 (30) 6 (15) 2 (5) 0
8 (20.5) 13 (33.3) 5 (12.8) 0
1.66 (0.59, 4.65) 0.35 (0.12, 1.05) 0.36 (0.07, 1.97) –
0.44 0.07 0.26 –
*Statistically significant. a All blood products + albumin 5%. b BE ≤ 6 and pH 18 s (1.59 normal) was significantly lower in the prophylactic compared to the reactive FPP strategy group at the end of surgery (2.9% vs 36.1%; P = 0.01). Similarly, the incidence of patients with a PTT value >43 s (29 normal) was lower in the prophylactic group at the completion of surgery (0% vs 12.8%; P = 0.026). Fibrinogen levels
ORIGINAL ARTICLE
Prophylactic versus reactive transfusion of thawed plasma in patients undergoing surgical repair of craniosynostosis: a randomized clinical trial Benjamin J. Pieters1, Lisa Conley1, Jennifer Weiford1, Marilyn Hamilton2, Brian Wicklund3, Adam Booser1, Adam Striker1, Susan Whitney1 & Virender Singhal4 1 2 3 4
Department of Anesthesiology, Children’s Mercy Hospital and Clinics, Kansas City, MO, USA Department of Pathology, Children’s Mercy Hospital and Clinics, Kansas City, MO, USA Department of Hematology-Oncology, Children’s Mercy Hospital and Clinics, Kansas City, MO, USA Department of Plastic Surgery, Children’s Mercy Hospital and Clinics, Kansas City, MO, USA
What is known
• Craniosynostosis repair in young children is associated with copious bleeding. • A dilutional coagulopathy is frequently observed requiring replacement of clotting factors with plasma. What this article adds
• Prophylactic plasma administration significantly increased the use of plasma and improved coagulation values but did not change blood loss or red cell transfusion requirements.
Implications for translation
• Timely transfusion of plasma according to current practice guidelines is adequate for hemostasis.
Keywords pediatrics; blood loss; craniosynostosis; blood component transfusion; fresh frozen plasma; blood volume Correspondence Dr. Benjamin J. Pieters, Department of Anesthesiology, Children’s Mercy Hospital and Clinics, 2401 Gillham Rd., Kansas City, 64108 Missouri, USA Email: [email protected] Section Editor: Andrew Davidson Accepted 21 October 2014 doi:10.1111/pan.12571
© 2014 John Wiley & Sons Ltd Pediatric Anesthesia 25 (2015) 279–287
Summary Background: Surgical repair of craniosynostosis in young children is associated with copious bleeding and often coagulopathy. Typically, a reactive transfusion strategy is used to treat coagulopathy whereby fresh frozen plasma (FFP) is given only after clinical manifestation of clotting abnormality. This prospective, randomized clinical trial was designed to test the hypothesis that prophylactic FFP during craniofacial surgery reduces blood loss and blood transfusion requirements compared to a reactive FFP transfusion strategy. Methods: Eighty-one patients less than 2 years of age requiring primary repair of craniosynostosis were randomized to receive FFP using either a prophylactic or reactive strategy. Laboratory values were measured at four standardized time points. The volume of blood products transfused, length of stay in the pediatric intensive care unit (PICU), hospital length of stay, and number of donor exposures were recorded for each patient. Results: The prophylactic FFP group received a significantly greater average volume of FFP compared to the reactive group (29.7 mlkg1 vs 16.1 mlkg1; P < 0.001), which was associated with improvement in coagulation values at multiple time points. However, there was no difference in blood transfusion requirements or blood loss between the two groups. The two transfusion strategies resulted in similar median donor exposures. There was no difference in PICU or hospital length of stay.
279
B. J. Pieters et al.
FFP during craniofacial surgery
Conclusion: A reactive FFP transfusion strategy required less plasma transfusion and was associated with similar rates of blood loss and PRBC transfusion as prophylactic FFP despite improvement in coagulation values in the prophylactic FFP group.
Introduction
Methods
The invasiveness of modern craniofacial surgery combined with the physiologic characteristics of younger children, notably a large head:body ratio and small blood volume, conspires to produce significant operative hemorrhage. Indeed, bleeding is the primary cause of morbidity and mortality associated with major craniofacial surgery (1). Predictable intraoperative periods, such as incising the scalp and elevation of bone flaps, are frequently associated with rapid blood loss requiring vigorous transfusion. Several blood conservation techniques have been used in an attempt to attenuate the often massive need for blood products in craniofacial surgery (2–8). However, the specific management of blood products in the OR remains debated in the literature and in clinical practice (9–11). Traditionally, plasma-poor packed red blood cells (PRBCs) are used for blood replacement. The use of such plasma-poor packed red cells can lead to clotting factor dilution, especially when given in the large volumes required for craniofacial surgery (12–16). Thus, clotting factor replacement, typically with fresh frozen plasma (FFP), is frequently necessary during craniofacial surgery and is usually given in a reactive manner once coagulation values have become abnormal. Given that blood loss averages close to one blood volume (17– 19), variability in bleeding is high, and it is difficult to predict outliers, it may be reasonable to give FFP routinely. Some authors advocate for the use of prophylactic FFP on the basis of improvement in postoperative coagulation values and improvement in clinical outcomes (10,13,20). Unfortunately, these recommendations are based on retrospective data. To test the efficacy of prophylactic FFP in the craniofacial surgical population, we have designed a prospective, randomized clinical trial comparing a traditional reactive FFP transfusion strategy (i.e., when laboratory and clinically defined coagulopathy is present) with prophylactic FFP transfusion. We hypothesized that administration of prophylactic FFP improves hemostasis and thereby decreases blood loss and red cell transfusion needs in children undergoing correction of craniosynostosis. Secondary outcomes include coagulation and arterial blood gas laboratory parameters, number of donor exposures, and pediatric intensive care unit (PICU) and hospital length of stay.
Approval for the study was obtained from the IRB at Children’s Mercy Hospital. Written informed consent was obtained from the legal guardian of 81 patients scheduled to undergo primary repair for craniosynostosis with either frontal orbital advancement (FOA) and/ or total calvarial reshaping and expansion (TCRE). Children were excluded for repeat craniofacial surgery, if they were older than 2 years at the time of surgery or if there was a history of complex congenital heart disease, coagulopathy, and liver or kidney disease. Craniosynostosis considered secondary to a syndrome was initially an exclusion criterion but later was removed with IRB approval in an attempt to improve the pace of accruement. The trial was not registered prior to patient enrollment because preenrollment registration was not required at the time the trial started. Red cell and hemostatic blood product transfusion was per protocol as was volume resuscitation. Briefly, when red cell transfusion was indicated, either by the blood product transfusion protocol (Table 1) or by the volume resuscitation protocol (Figure 1), the prophylactic group received PRBCs and FFP in equal volumes (10 mlkg1 each product) to ensure an adequate volume of each blood product to be clinically meaningful in a 1 : 1 PRBC : FFP ratio. The reactive transfusion group received PRBC (10 mlkg1) only, when blood transfusion was indicated. As volume status dictated additional boluses of colloid as specified in Figure 1, both groups were balanced in terms of colloid administration for the intraoperative period. Consistent with common clinical practice, 15 mlkg1 of FFP was transfused if criteria in Table 1 were met. Both the surgeon and the anesthesia team had to agree to give FFP if the decision was based only on the clinical criteria in Table 1. Given that PRBC units usually have a larger volume than FFP units, it was allowable to give the last part of a PRBC unit (≤50 ml) without FFP in the prophylactic group in order to minimize FFP waste. Factor VIIa was included in the study protocol as a rescue agent because of a recommendation by the hematology department at our institution. Cryoprecipitate was not part of the intraoperative study protocol. We used a single-donor program that has previously been described at out institution (21) whereby units of PRBC and FFP can be obtained from the same donor.
280
© 2014 John Wiley & Sons Ltd Pediatric Anesthesia 25 (2015) 279–287
B. J. Pieters et al.
Table 1 Volume resuscitation protocol 1. PRBC transfusion criteria: a. Hb 27 do not transfuse PRBC 2. FFP transfusion criteria: a. Signs and symptoms of coagulopathy/microvascular bleeding and (time permitting): b. PT > 18 s or PTT > 43 s or fibrinogen < 100 then transfuse FFP 15 mlkg1 3. Platelets transfusion criterion: a. Platelet count 35.5°C. Standard ASA monitors were used as well as an arterial blood pressure catheter and a urinary catheter in all cases and a central venous catheter at the discretion of the anesthesiologist. Anesthesia was maintained with isoflurane (endtidal minimum alveolar concentration = 0.75–1.5) in an oxygen and air mixture, remifentanil infusion 0.1– 0.5 mcgkg1h1, and rocuronium. Patients were mechanically ventilated to maintain normocapnia. Surgical correction consisted of frontal orbital advancement, total calvarial reshaping and expansion, or both. Epinephine 1 : 100 000 was injected by the surgeon prior to surgical incision. All procedures were performed by the same surgeon. Preoperative fluid deficit was calculated as maintenance fluid (4, 2, 1 method) multiplied by the number of hours nil per os. Deficit volume was replaced with lactated ringers: half of the deficit in the first hour of surgery and one-fourth of the deficit for each of the next 2 h. Maintenance fluid was provided as an infusion of Plasma-Lyte 148 at the rate calculated above during the entire surgical procedure. Thawed plasma was brought to the OR along with the first unit of PRBC in both groups and was suspended from an IV pole after being placed in an opaque plastic bag to blind the surgeon to group allocation and thus reduce requests for FFP transfusion based on clinical criteria alone, for example, microvascular bleeding on the field. Intraoperatively, arterial blood gas measurement was obtained at least hourly and more often at the discretion of the anesthesiologist. A CBC and coagulation panel (protime, partial thromboplastin time, and fibrinogen) were obtained at four standardized times for each patient: approximately 2 weeks prior to surgery (T1), intraoperatively after all skull bone removal (T2), immediately postoperatively (T3), and six hours postoperatively (T4). Goal Hct for the end of the surgery was 28%. At the end of surgery, patients were taken to the postanesthesia care unit (PACU) and extubated awake. After initial stabilization in the PACU, patients were transferred to the pediatric intensive care unit (PICU) for overnight observation, as per standard care at our institution. Treatment of coagulation parameters and blood transfusion while the patient was in the pediatric intensive care unit (PICU) were not strictly protocolized, rather it was recommended that transfusion of blood occurs for hematocrit 18 or PTT >43. Cryoprecipitate was not part of the study 281
B. J. Pieters et al.
FFP during craniofacial surgery
protocol and its use, as well as transfusion of all blood products while the patient remained in the PICU, was ultimately up to the discretion of the PICU team, who were not blinded to group allocation. The triggering hematocrit immediately prior to transfusion in the PICU was recorded to allow comparison between groups. Blood loss was calculated as previously described for craniosynostosis repair (6,16,22) according to the formula: ERCVlost ¼ ERCVpreop þ ERCVtransfused ERCVpostop Where ERCV (estimated red cell volume) = Estimated blood volume 9 hematocrit/100. A value of 80 mlkg1 was used for estimated blood volume for all patients. ERCVtransfused = 0.66 9 PRBC transfused (ml) intraoperatively as the average hematocrit of PRBC units at our institution is 66%. Parametric and nonparametric data were presented as mean and standard deviation or median and range, respectively. Differences were calculated using two-sided t-test for parametric data or Wilcoxon rank sum for nonparametric data. Categorical data were compared using Fisher’s exact or chi-square test as appropriate and are represented as frequency and percent. Additionally, absolute difference in mean or odds ratio and corresponding 95% confidence intervals were calculated, if possible, for continuous and binary variables, respectively. Power analysis was undertaken with the assumption that a 25% reduction in blood transfusion would be clinically significant. Two-sided a was assigned at P < 0.05 as the criterion for statistical significance. With 40 patients per group, there would be 80% power to detect a significant difference between groups. Statistical analyses were performed using SAS software version 9.2 (SAS, Cary, NC, USA). Results A total of 81 patients ranging in age from 6 to 23 months were prospectively enrolled between July 2007 and September 2012. All patients were randomized to either the treatment group (N = 41) or the control group (N = 40). Two patients, one in the control group and one in the treatment group, experienced extreme hemodynamic instability intraoperatively resulting in the anesthesia provider being unable to comply with the study protocol. Two analyses were performed: a per-protocol analysis excluding the two protocol violation patients, and an intention to treat analysis including all patients. The results did not change significantly by type of analysis, and for the 282
sake of concision, the results are reported for the per-protocol analysis only with the exception of our primary outcome variable transfusion of PRBC, for which both data sets are reported. Groups were similar with respect to demographic and surgical characteristics (Table 2). As shown in Table 3, the two groups received virtually identical volumes of crystalloid and there was no significant difference in volume of total nonred cell colloid (albumin + FFP) administered in the operative period. However, the relative distribution of type of colloid differed with greater albumin and less FFP in the reactive group and the opposite trend in the treatment group (Tables 3 and 4). In fact, the prophylactic strategy resulted in significantly more FFP transfusion, both in terms of percent of patients receiving FFP (100% vs 74%; P = 0.003) and mean volume of FFP given per group (29.7 mlkg1 vs 16.1 mlkg1; P < 0.001). The prophylactic group did not require any additional administration of FFP beyond that given with PRBCs, that is, the study intervention. The reactive group received FFP in 15 mlkg1 boluses as per Table 1 criteria with two patients (5%) requiring transfusions based only on clinical criteria and the remainder according to both clinical and laboratory criteria. All patients received PRBCs perioperatively. Hematocrit levels measured at standardized time points designated T1–T4 are presented in Table 5 and showed no significant difference between groups, indicating compliance with a strict red cell transfusion protocol. Perioperative blood product totals are summarized in Table 4. The two groups did not differ significantly in PRBC transfusion or estimated red cell volume loss. There were 17 patients in the reactive transfusion group who required PRBC postoperatively with average measured postoperative Hct prior to transfusion of 23.1%, while 20 patients in the prophylactic group received PRBC postoperatively with pretransfusing Hct of 22.8% (P = 0.78). In the PICU, cryoprecipitate was given to four of the reactive group patients and none of
Table 2 Baseline demographics
Age (months) Weight (kg) Gender (M/F) Syndrome present Y/N FOA/TCRE/Both Length of surgery (min)
Prophylactic Group (N = 40)
Reactive Group (N = 39)
12.1 3.9 9.9 1.8 24/16 1/39 16/22/2 234 29.8
11 2.7 9.3 1.4 19/20 3/36 10/29/0 225 26.4
FOA, Frontal orbital advancement; TCRE, Total calvarial reshaping and expansion. © 2014 John Wiley & Sons Ltd Pediatric Anesthesia 25 (2015) 279–287
B. J. Pieters et al.
FFP during craniofacial surgery
Table 3 Intraoperative fluid and metabolic parameters Fluid parameter
Prophylactic Group (N = 40)
Blood volume lost (%) Crystalloid (mlkg1) Albumin 5% (mlkg1) Total Colloid (mlkg1)a Urine output (mlkg1h1)
102 57.2 17.1 80 2.3
Metabolic parameter 1
Ca < 1 mmoll BE ≤ 6 mmoll1 Metabolic acidosisb Sodium ≤130 mmoll1 ++
45.4 13.4 14.2 37.4 1.6
Reactive Group (N = 39) 95.8 57.7 28.6 77 2
51 13.7 16.5 45.9 1.7
Difference in mean (95% CI)
P value
19.56 (103.6, 64.47) 0.48 (5.59, 6.55) 11.54 (4.65, 18.43) 2.98 (21.7, 15.74) 0.23 (0.96, 0.51)
0.57 0.88 0.001* 0.66 0.54
n (%)
n (%)
Odds ratio (95% CI)
P value
12 (30) 6 (15) 2 (5) 0
8 (20.5) 13 (33.3) 5 (12.8) 0
1.66 (0.59, 4.65) 0.35 (0.12, 1.05) 0.36 (0.07, 1.97) –
0.44 0.07 0.26 –
*Statistically significant. a All blood products + albumin 5%. b BE ≤ 6 and pH 18 s (1.59 normal) was significantly lower in the prophylactic compared to the reactive FPP strategy group at the end of surgery (2.9% vs 36.1%; P = 0.01). Similarly, the incidence of patients with a PTT value >43 s (29 normal) was lower in the prophylactic group at the completion of surgery (0% vs 12.8%; P = 0.026). Fibrinogen levels
