Article Text

Download PDFPDF

Fresh frozen plasma use in the NICU: a prospective, observational, multicentred study
  1. Mario Motta1,
  2. Antonio Del Vecchio2,
  3. Barbara Perrone3,
  4. Stefano Ghirardello4,
  5. Maurizio Radicioni5
  1. 1Children's Hospital of Brescia, Brescia, Italy
  2. 2Ospedale Di Venere, Bari, Italy
  3. 3“G.Salesi” Children's Hospital, Ancona, Italy
  4. 4Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milano, Italy
  5. 5Santa Maria della Misericordia Hospital, Perugia, Italy
  1. Correspondence to Dr Mario Motta, Neonatology and Neonatal Intensive Care Unit, Children's Hospital of Brescia, P.le Spedali Civili, Brescia 25123, Italy; mario.motta{at}spedalicivili.brescia.it

Abstract

Objectives To examine the use of fresh frozen plasma (FFP) in Italian neonatal intensive care units (NICUs); specifically to quantify compliance with guideline recommendations and to evaluate the relationship between coagulation tests and subsequent bleeding episodes.

Design Prospective, observational study.

Setting Seventeen Italian NICUs.

Patients and methods Over a period of 12 months, for all neonates that received FFP we recorded specific characteristics, pretransfusion and post-transfusion laboratory test of haemostasis, and details of all haemorrhagic events.

Results Among 3506 NICU admissions, 290 (8.2%) received one or more FFP transfusions during their hospital stay. Of these, 37% received FFP because of active bleeding and 63% received FFP prophylactically with the intention of preventing haemorrhage. A total of 609 FFP transfusions were administered (mean 2.1/transfused patient—range 1–25). Using previously agreed upon criteria, we judged that 60% of the 609 FFP transfusions were not compliant with guideline recommendations. By logistic regression, abnormalities in the prothrombin time, activated partial thromboplastin time, fibrinogen and platelet count were not independently associated with bleeding episodes.

Conclusions FFP transfusion is a relatively frequent intervention in the NICU. In the present analysis, we found a remarkably high proportion of FFP transfusions given to non-bleeding neonates for indications not compliant with guideline recommendations. Platelet counts and coagulation studies were poor predictors of clinical bleeding.

  • Newborn
  • Plasma
  • Blood Component Transfusion
  • Hemorrhage
  • Hemostasis

Statistics from Altmetric.com

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

What is already known on this topic

  • The use of fresh frozen plasma (FFP) in neonatal intensive care units (NICUs) is not evidence-based and practice varies.

  • Coagulation testing is sometimes used to identify candidates for FFP transfusion.

What this study adds

  • During a 12-month period, 8.2% of newborns cared for in 17 Italian NICUs received one or more FFP transfusions.

  • Of these transfusions, 60% were non-compliant with published guidelines.

  • Coagulation testing did not predict subsequent clinical haemorrhage.

Introduction

The use of fresh frozen plasma (FFP) in neonatal intensive care units (NICUs) appears to be a frequent intervention despite a lack of supporting evidence. In a recent study from England, Stanworth et al1 showed that 2.3% of all patients receiving FFP were children (aged 1–15 years) and 4.4% of these were less than 1 year old. He also reported that 62% of infants who received FFP did not have clinical bleeding and that 14% of infants treated with FFP did not have coagulation tests before the FFP administration.1 Puetz et al2 reported that FFP was administered to 2.85% of admissions to paediatric hospitals in the USA and that 29% of these transfusions were given to neonates.

A variety of guidelines on transfusion of blood components in neonates have been published.3–5 In 2002, Roseff et al3 reviewed the appropriateness of transfusions in paediatric populations, including recommendations of FFP transfusion that were mainly based on expert opinion. In 2004, the British Committee for Standards in Haematology updated its document on transfusion guidelines for neonates and older children.4 In this document, the strength of recommendations was graded by using the quality of evidence and, apart from a few conditions where the use of FFP is not supported by results of controlled clinical studies, the recommended indications for FFP transfusion were characterised by a low level of evidence.

Although guidelines highlight that the use of plasma products in neonates should be limited to specific conditions, the lack of scientific evidence in the majority of clinical settings may lead to a wide variety of transfusion practice among neonatologists.

We previously reported results of a national Italian survey on neonatal transfusion practice, where 11% of NICUs reported administering FFP for clinical indications alone without coagulation testing. We also reported that 26% of NICUs administered FFP outside guideline-based indications.6 Several reports have evaluated the potential usefulness of FFP transfusions in neonates7 ,8; however, detailed data are lacking. Consequently, we aimed to (1) prospectively quantify FFP usage in representative Italian NICUs, (2) judge the appropriateness of each FFP administration according to preset guidelines, (3) describe and quantify all haemorrhagic episodes among FFP-transfused neonates and (4) statistically assess associations between potential risk factors and actual bleeding episodes.

Methods

Participating centres, study subjects and ethical approval

In total, 17 (21.5%) out of 79 tertiary-level NICUs in Italy participated in this study. All neonates in these NICUs who received a FFP transfusion were eligible for prospective enrolment. Participating NICUs supported recruitment for a 12-month period from January 2011 to February 2012. The study was approved by the Ethics Committee of the Children's Hospital of Brescia, which was the coordinating study centre. Written informed consent was obtained from the parents of all neonates included in the study.

Data collection and statistical analysis

Baseline data included gestational age, birth weight, postnatal age at transfusion, dose (mL/kg) of FFP administered, pretransfusion and post-transfusion laboratory tests of haemostasis, including prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen and pretransfusion platelet count. Pretransfusion and post-transfusion laboratory tests of haemostasis were considered as those tests performed within 24 h before and up to 24 h after FFP administration. A list of potential indications for FFP use (compliant and non-compliant with guideline recommendations) was included in the data collection form (table 2). For each FFP transfusion administered, the indication for the transfusion was recorded from an attending senior neonatologist during or immediately after ordering.

Haemorrhage as an indication for FFP was classified as intraventricular haemorrhage (IVH), pulmonary haemorrhage, gastrointestinal haemorrhage or minor haemorrhage. IVH was diagnosed by cranial sonography and graded by the classification of Papile et al.9 Pulmonary haemorrhage was defined as a significant amount of blood suctioned from the endotracheal tube with a chest radiograph consistent with pulmonary bleeding. Gastrointestinal haemorrhage was defined as a significant amount of blood suctioned from the stomach or repeated episodes of haematochezia or melena. Minor haemorrhage included mucocutaneous bleeding, such as light blood staining of oral, nasogastric or endotracheal secretions, or the occurrence of microhematuria or ecchymosis.

The timing of cranial sonography and the specific laboratory assessments of haemostasis were not mandated by the study.

All data were reviewed by the coordinating study centre, and the indications of each FFP administration were grouped as compliant or non-compliant with respect to published standards and guidelines for neonatal transfusion.3–5 In addition, in order to compare the mortality rate of FFP transfusion recipients with that of the general NICU population, data on the total number of neonatal admissions and on the total neonatal mortality rate during the study period were collected from each NICU participating in the study.

The characteristics of study neonates were analysed by descriptive statistics. Continuous variables with symmetrical distribution were presented as mean±SD, continuous variables with asymmetrical distribution were presented as median and interquartile range and categorical variables were presented as absolute number and percentage. Comparisons between pretransfusion and post-transfusion values of PT, APTT and fibrinogen were performed by Mann–Whitney U test. Transfusion events were grouped according to different types of haemorrhagic episodes, as specified above, and characteristics of each different subgroups were compared with the group of FFP-transfused neonates without bleedings using Mann–Whitney U or Fisher's exact tests. Logistic regression analysis was used to evaluate the possible association between gestational age, birth weight and pretransfusion values of PT, APTT, fibrinogen and platelet count as continuous independent variables, and the occurrence of different subtypes of haemorrhages as categorical dependent variables. All computations were performed using two statistical packages (Statistica, StatSoft, Tulsa, Oklahoma, USA; MedCalc for Windows, Mariakerke, Belgium). All results were considered statistically significant at p<0.05.

Results

During the 12-month study period, the 17 NICUs admitted 3506 neonates and a total of 609 FFP transfusions were administered to 290 (8.2%) neonates. Among the 17 NICUs, the percentage of neonates who received FFP ranged from 2.5 to 20 of admissions (median 8.7%). The mean number of transfusions/patient was 2.1 (range 1–25). Those who received one or more FFP transfusions had a significantly higher mortality rate than did those with no FFP transfusions (25.5% vs 3.4%; p<0.001), and they had an increased OR for mortality 6.3 (95% CI 4.9 to 7.8).

Characteristics of neonates who received FFP, and the recorded indications for these, are shown in tables 1 and 2. Among the 290 who received FFP, 107 (37%) had at least one bleeding episode, while 183 (63%) had no bleeding episodes. In total, 244 (40%) FFP transfusions were given for indications that we judged as compliant, whereas 365 (60%) were non-compliant with guideline recommendations. Among the compliant indications, the main causes of multiple transfusions were liver failure and disseminated intravascular coagulation (table 2).

Table 1

Characteristics, pretransfusion tests of haemostasis (according to gestational age at birth) and variety of haemorrhage among 290 neonates that received FFP transfusion

Table 2

Indication for administering 609 FFP transfusion events according to guidelines on blood components for neonatal transfusion

Forty-two per cent of FFP transfusions were administered in the first 3 days; half by day 5, 75% by day 14 and 90% by day 28.

Pretransfusion and post-transfusion tests of haemostasis were available for 329 and 189 transfusion events, respectively (tables 1 and 3). As shown in table 3, PT and APTT values were significantly longer before versus after FFP administration. In neonates born less than 28 weeks’ gestation, and in those 28–34 weeks, the pretransfusion and post-transfusion values of fibrinogen were similar (table 3). In contrast, fibrinogen values were significantly lower before versus after FFP administration in neonates more than 34 weeks’ gestational age at birth (table 3).

Table 3

Comparison between 189 pretransfusion and post-transfusion PT, APTT and fibrinogen values in neonates who received FFP, according to gestational age at birth

As shown in table 4, by univariate analysis, gestational age and birth weight were significantly lower and APTT longer, in neonates with all grades of IVH, compared with those with no haemorrhage. Mechanical ventilation and patent ductus arteriosus were more frequent among those with IVH. However, no differences were found in PT, fibrinogen or platelet count between those who had versus those who did not have IVH. Results were similar for neonates with grade 3 or 4 IVH compared with those with no haemorrhage. Neonates with pulmonary haemorrhage had significantly higher gestational age and birth weight and significantly longer PT and lower fibrinogen values. Pulmonary haemorrhage was more frequent among those who required mechanical ventilation. Coagulation times were significantly longer in those with gastrointestinal haemorrhage. The group with minor haemorrhage had longer coagulation times, lower fibrinogen and lower platelets.

Table 4

Univariate analysis comparing characteristics and pretransfusion laboratory tests of haemostasis of neonates with and without haemorrhage

As shown in table 5, by logistic regression, the occurrence of all grades IVH was associated with lower gestational age, and minor bleeding episodes were associated with higher gestational age. The occurrences of IVH grade 3 or 4, pulmonary haemorrhage and gastrointestinal haemorrhage were not independently associated with gestational age, birth weight, clotting times, fibrinogen or platelet count.

Table 5

Relationships between haemorrhage, characteristics of neonates and pretransfusion laboratory tests of haemostasis

Discussion

This study provides prospective information on the use of FFP in 17 NICUs in Italy and is based on 609 transfusions administered to 290 neonates. We found FFP administration to be a relatively frequent intervention, with 8% of admitted neonates receiving one or more. Retrospective studies by Baer et al10 and Puetz et al11 reported a similar rate of FFP transfusion in NICUs; 6% and 12%, respectively. In addition, both reported a significant proportion of use noncompliant with published recommendations. Altuntas et al12 reported a lower rate of 2%; however, the usage outside of guidelines was high.

In this study, the sixfold increase in risk of death of FFP-transfused neonates likely reflects sicker patients. However, we cannot confirm this as the explanation. A remarkably high proportion (60%) of transfusions were non-compliant with guidelines and 63% of transfused neonates received FFP prophylactically, without bleeding episodes.

However, when considering the rate of compliance with guidelines, it is important to note that guideline recommendations used for this study are mainly based on poor quality evidence. In addition, some guideline recommendations such as the liver failure and disseminated intravascular coagulation, which were the clinical conditions associated with the highest rate of multiple transfusions of term neonates in our study, are non-evidence-based recommendations. In addition, the wide variability of the percentage of FFP recipients among different NICUs observed in our study, which ranges from 2.5% to 20% of admitted neonates, may reflect the lack of acceptable criteria for FFP transfusion.

The most frequent haemorrhage reported as an indication for FFP was IVH of all grades (18.6% of FFP-transfused neonates), which occurred exclusively in preterm neonates; however, grade 3 or 4 IVH was reported in a minor percentage (6.6%) of FFP-transfused neonates. Pulmonary haemorrhage (5.5% of transfused neonates) occurred mainly in term neonates.

The relatively late onset of gastrointestinal haemorrhage (median of 10 days postnatal age) may be partly explained by necrotising enterocolitis in 20% of cases (data not shown). The mean volume of FFP administered in our study was 16 mL/kg, which is in accordance with our recommendations for neonatal transfusion practice.5 This volume was sufficient to affect the PT and APTT (table 3). In contrast, in preterm neonates (gestational age less than 35 weeks at birth), the FFP transfusions did not significantly increase the fibrinogen value. However, the relationship between these laboratory coagulation tests and the actual clinical risk of haemorrhage is unclear. Although our univariate analysis showed longer coagulation times in bleeding neonates, other differences between the two groups may be considered concomitant causative factors of bleeding. Specifically, the lower gestational age in neonates with IVH, the higher need of mechanical ventilation in neonates with pulmonary haemorrhage and the lower platelet counts in neonates with cutaneous haemorrhage may contribute to the pathogenesis of their bleeding. The multivariate analysis indicated that no laboratory tests of haemostasis were associated with haemorrhage, while IVH all grades were significantly associated with lower gestational age and minor haemorrhages with higher gestational age. These findings suggest a multifactorial pathogenesis of bleeding. Our findings are consistent with the results obtained in a recent study of Christensen et al,13 where abnormal coagulation values drawn at delivery did not predict clinical bleeding episodes during the first week, suggesting that bleeding in the days following preterm birth is not generally the result of in utero coagulopathy.

Another reason that could explain the lack of association between coagulation times and haemorrhagic episodes is the poor predictive value of PT and APTT regarding bleeding risk. In our opinion, the role of conventional coagulation tests as predictors of bleeding in neonates requires additional investigation. In fact, questions have been raised regarding the meaning of the PT and APTT in neonates.14 These tests do not account for the physiologically lower concentrations of anticoagulants (protein C and ATIII) in neonates, and therefore do not reflect the actual balance between procoagulant and anticoagulant factors. In a study by Tripodi et al,15 the coagulation system of neonates appears to be normal and balanced between procoagulants and anticoagulants despite prolongations of the PT and APTT. This finding is consistent with the results obtained in neonates by thromboelastography. Specifically, in spite of apparent prolongation of the PT and APTT, clot reaction times by thromboelastography, which are expressions of the enzymatic phase of coagulation, were normal and significantly shorter in neonates than in adults, suggesting a normal thrombin generation potential.16

We recognise important limitations of our study. First, our data come from Italian NICUs and therefore may not be representative of other populations or national practices. Second, as an observational study, data were collected only on neonates who received FFP transfusions; therefore, we lack some potentially useful control comparisons. Finally, although we found a significantly increased mortality rate among FFP recipients, we were unable to identify the factors responsible for this finding.

Despite the study limitations, we maintain that these new data are useful in highlighting the uncertain rational for FFP administration to neonates, and raising questions about its appropriateness and effectiveness in this population. Surely, better diagnostic tests would move this work forward, permitting a more confident detection of neonates with coagulopathies potentially treatable with FFP.

Moreover, our data support the need for high-quality controlled studies (ie, randomised clinical trials in accordance with the CONSORT statement) in order to improve the current knowledge on the effect of FFP and to define better the appropriateness of the recommendations for its use in neonatal transfusion medicine.

Acknowledgments

The authors gratefully acknowledge Dr Robert Christensen (Women and Newborn’s Clinical Program, Intermountain Healthcare, Salt Lake City, Utah, USA) for thoughtful critique of the manuscript. The authors thank all participating neonatal centres: Daniela Regoli, Università Sapienza—Roma; Marina Battaglioli, Buzzi Children’s Hospital—Milano; Marcella Testa, Azienda Ospedaliera and University of Cagliari; Francesco Raimondi, University Federico II—Napoli; Lidia Decembrino, Policlinico San Matteo—Pavia; Laura Barberis, S Anna Hospital—Torino; Daniela Ferrari, Azienda Ospedaliera—Cremona; Antonio Scorrano, Azienda Ospedaliera Cardinale G Panico—Tricase; Lucia Taurino, Azienda Ospedaliero-Universitaria—Foggia; Mariarosaria Berti, Azienda Provinciale Servizi Sanitari—Trento; Anna Casani, G Rummo Hospital—Benevento; Luigi Corvaglia, St. Orsola-Malpighi University of Bologna; Sara Gavioli, Arcispedale Santa Maria Nuova—Reggio Emilia; Elisa Dusi, Ospedale Maggiore Policlinico di Milano.

References

Footnotes

  • Collaborators Daniela Regoli, Marina Battaglioli, Marcella Testa, Francesco Raimondi, Lidia Decembrino, Laura Barberis, Daniela Ferrari, Antonio Scorrano, Lucia Taurino, Mariarosaria Berti, Anna Casani, Luigi Corvaglia, Sara Gavioli and Elisa Dusi.

  • Contributors All authors are responsible for reported research. All authors have participated in the concept and design; analysis and interpretation of data; drafting or revising of the manuscript; and they have approved the manuscript as submitted.

  • Competing interests None.

  • Patient consent Obtained.

  • Ethics approval Ethics Committee of the Children's Hospital of Brescia.

  • Provenance and peer review Not commissioned; externally peer reviewed.