surgery on cardiopulmonary bypass: A systematic review and meta-analysis.

(1)

Electronic Supplement for:

Antifibrinolytic drugs for the prevention of bleeding in pediatric cardiac

surgery on cardiopulmonary bypass: A systematic review and meta-analysis.

Siemens et al.

Electronic Supplement 1:

Review Protocol Systematic Review and Search Terms

( v1 02/06/2014, authors: Kristina Siemens, Dilanee Sangaran)

Background

Perioperative mediastinal bleeding is common in children undergoing cardiac surgery on cardiopulmonary bypass and is associated with hemodynamic instability, prolonged operation time, potential chest re-exploration and increased transfusion requirements. (1) Allogeneic blood transfusion is an independent contributor to postoperative morbidity with a higher incidence of adverse outcomes for children compared with adults. (79-84) Large amounts of the available blood supply are spent on cardiac surgery. An audit in an Australian tertiary paediatric hospital demonstrated that cardiac surgery on bypass was the greatest user of red blood cell (RBC) units with transfusion occurring in 79% of all procedures. (85) In the UK New

(2)

An initial search for reviews on management of bleeding in children after cardiopulmonary bypass (CPB) brought up a few comprehensive narrative reviews as well as systematic reviews focusing on specific aspects such as the use of antifibrinolytics. The multi-factorial aetiology of bleeding after cardiac surgery on CPB suggests a multi-faceted, interdisciplinary approach. No comprehensive systematic review examining all available strategies was found.

From clinical experience and evidence in the current literature the need for such a review was identified. As a first approach we have chosen to conduct a scoping review to systematically identify and describe this broad and heterogeneous body of evidence to then focus on more specific aspects in smaller, more distinct systematic reviews.

The initial rational behind this review was formulated by the lead author, who subsequently recruited the co-author. There was no commercial support or influence and we had full control of the ideas, data reporting and conclusions of the research. As this was a synthesis of previously published literature, it was except from requirement for ethic committee approval.

Question

The objective of this review is to map studies assessing strategies for prevention and early management of perioperative bleeding in children undergoing cardiac surgery on cardiopulmonary bypass compared to current practice.

Eligibility Criteria

Studies are included if they report a predefined outcome of strategies for perioperative prevention and early management of bleeding.

Perioperative is defined as the day of surgery +/- one day and therefore in particular comprises the scope of work of the anaesthetic, surgical and intensive care team.

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Studies are eligible if participants were neonates and children < /= 18 yrs undergoing cardiac surgery on cardiopulmonary bypass. Studies in mixed adult and paediatric patients are included, if outcomes are reported separately for children under 18 years of life.

Cardiac surgery for congenital and non-congenital heart disease is included, excluding studies involving cardiopulmonary bypass for non-cardiac surgery. We also exclude studies of patients with congenital clotting factor deficiencies, sickle cell disease or other haematological disorders. The rational for the exclusion of these subgroups is the different risk profile and individual needs in management compared to the main population.

Any intervention or combination of interventions given for the prevention and early management of perioperative bleeding are included.

This comprised pharmacological and non-pharmacological strategies such as blood product use (platelet concentrates, cryoprecipitate, FFP, whole blood), cell saver blood, age of blood products, transfusion guidelines, antifibrinolytics (aprotinin, tranexamic acid, ε-aminocaproic acid), coagulation factor concentrates (prothrombin complex concentrate, FVII, fibrinogen concentrate), anticoagulation (heparin, hirudin), protamine, Vitamin K, topical agents, delayed chest closure, monitoring via ACT, ROTEM/TEG, modification of CPB circuits (priming, coating, size filters) or ultrafiltration. Anticoagulants are included on the background that prevention of intravascular coagulation with consecutive consumption of coagulation factors

(4)

is chosen in reflection of the often very variable practice between different centres and lack of overarching guidelines.

Outcomes of interest include (but are not restricted to) ‘intraoperative bleeding’ (including the impression of surgeon/anaesthetist ‘oozy’, ‘wet’), postoperative bleeding (drain losses, pericardial effusions/tamponade), chest closure times, chest re-exploration, transfusion requirements, reduction in inflammatory response to CPB and therefore secondary prevention of bleeding, thrombosis, secondary bleeding, length of stay PICU and mortality.

Scoping searches revealed that there are likely to be only a limited number of relevant randomised studies. To take account of the paucity of studies we therefore in the initial search include all study types (RCTs, non-RCTs, prospective comparator studies, retrospective comparator studies, prospective and retrospective non-comparator studies, case reports and reviews) with no restrictions to language and publication status. Preclinical studies are excluded due to the clinical scope of this review. Eligible studies are restricted to those published between the years 1980 and 2016.

For the detailed analysis we then exclude case reports and reviews. Studies published as abstract only or with a full text in non-English language are also excluded from the final analysis, even though controlled studies will be included in the reference list for completeness.

Search sources and strategy

Eligible studies were identified in MEDLINE, EMBASE, PubMed and the Cochrane CENTRAL Register. Our Search Strategy is built on the PICOS question as stated above.

Study Selection

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The study selection will be conducted in two stages. Initially titles and abstracts of identified studies are screened for relevance, followed by screening of the full papers, identified as possibly relevant in the initial screening, assessed against the formal eligibility criteria.

Titles and abstracts identified through the initial search will be screened for relevance by two authors (K.S., D.S.), who then independently assessed the full publications of the potentially relevant studies against the formal eligibility criteria. Potential disagreements were resolved by consensus and failing that a third reviewer (S.T., I.M.) was able to arbitrate.

Data extraction

Data from eligible studies were then extracted using a standard data collection sheet, providing information on the author, type of publication, country of origin, language, source of funding, the centre/s where the study had been conducted, study type, number of participants, patient cohort, inclusion/exclusion criteria, methodology, interventions assessed, comparator, objectives, outcomes, and conclusion.

Appraisal of quality of included studies

For critical appraisal of selected RCTs and observational studies the CASP (Critical Appraisal Skills Programme) Checklist for Trials and the GRADE (Grading of Recommendations, Assessment, Development and Evaluations) system were applied by the two independent

(6)

We report continuous data as medians (interquartile range (IQR)), and binary data as count (percent). Where these are not reported in the original publications, they can be obtained from other given data as described in the Cochrane Handbook. We use linear regression to evaluate the changes over time in the number of trials published.

Dependant on the available studies and data a meta-analysis was planned.

When relevant data were available statistical analysis was performed using Review Manager 5 software (REVMAN 5; The Cochrane Collaboration, Oxford, UK).

As some outcome data did not allow for meta-analysis, these were reported descriptively. A summary of findings table was produced for all the studies included in the meta-analysis. This used the software in REVMAN 5 as suggested in the Cochrane Handbook for Systematic Reviews of Interventions. All studies considered for the meta-analysis were assessed for possible risk of bias, using the ‘Risk of bias’ tool as described in chapter 8 of the Cochrane Handbook of Systematic Reviews of Interventions. Risk of bias was assessed on a three point scale: low, high or unclear. Furthermore, publication bias was assessed using funnel plot analysis.

Where original data were expressed as continuous variables, the mean and standard deviation were recorded. A random effects model was used to compute the mean difference using REVMAN 5. All outcomes were noted as differences compared with the placebo or control. Where dichotomous data were used, a risk ratio was generated using the Mantel-

Haenszel method. Heterogeneity was assessed using I2-statistics; according to the Cochrane

review guidelines, I2 > 40% and P < 0.01 were considered threshold values for heterogeneity, indicating the presence of a random effects mean difference computation. In studies with several comparison groups with different drugs, each one was considered as a separate study in the meta-analysis and compared with the split control group. Where several

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comparison groups within one study used the same drug but more than one dosing scheme, a single pair-wise comparison was undertaken. In studies with more than one dosage scheme, each one was considered as a separate study in the meta-analysis and compared with the control group. Where several comparison groups existed within one study, a single pair-wise comparison was undertaken.

Subgroup and sensitivity analyses were performed for computed data as well as for studies with different dosing regimens.

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Search Terms

Ovid Medline

((neonat* or child* or paediatric* or pediatric* or infant* or newborn* or adolescent* or juvenile or congenital or exp child/ or exp infant/ or exp adolescent/ or exp pediatrics/)

and

('cardiopulmonary bypass' or 'heart bypass' or 'heart-lung-machine' or exp 'cardiopulmonary bypass'/

or 'cardiac surgery' or 'heart operation' or exp 'heart surgery'/) and

(hemorrhag* or 'blood loss' or bleeding or coag* or clot* or hemostasis or haemostasis or transfus* or exp bleeding/ or exp hemorrhage/ or exp hemostasis/ or exp haemostasis/)

and

(treat* or therapy* or therapeutic* or manage* or transfus* or threshold or restrict* or practic* or polic*

or strateg* or guideline* or indication* or protocol* or prevent* or prophyla* or 'blood sparing' or 'cell saver' or 'cell salvage' or 'blood component' or 'blood clotting factor*' or exp 'hematologic agent'/ or exp 'anticoagulant agent'/ or exp 'fibrinolytic agent'/ or exp 'hemostatic agent'/ or exp 'plasma substitute'/ or exp 'antifibrinolytic agent'/ or exp ' heparin antagonist'/ or exp 'antithrombocytic agent'/ or exp 'blood'/

or exp 'blood component'/ or exp 'blood transfusion'/ or exp 'blood clotting factors'/)).tw.

(9)

Ovid EMBASE

((neonat* or child* or paediatric* or pediatric* or infant* or newborn* or adolescent* or juvenile or congenital or exp juvenile/ or exp child/ or exp infant/ or exp adolescent/ or exp pediatrics/)

and

('cardiopulmonary bypass' or 'heart bypass' or 'heart-lung-machine' or exp 'cardiopulmonary bypass'/

or 'cardiac surgery' or 'heart operation' or exp 'heart surgery'/) and

(hemorrhag* or 'blood loss' or bleeding or coag* or clot* or hemostasis or haemostasis or transfus* or exp bleeding/ or exp hemorrhage/ or exp hemostasis/ or exp haemostasis/)

and

(treat* or therapy* or therapeutic* or manage* or transfus* or threshold or restrict* or practic* or polic*

or strateg* or guideline* or indication* or protocol* or prevent* or prophyla* or 'blood sparing' or 'cell saver' or 'cell salvage' or 'blood component' or 'blood clotting factor*' or exp 'hematologic agent'/ or exp 'anticoagulant agent'/ or exp 'fibrinolytic agent'/ or exp 'hemostatic agent'/ or exp 'plasma substitute'/ or exp 'antifibrinolytic agent'/ or exp ' heparin antagonist'/ or exp 'antithrombocytic agent'/ or exp 'blood'/

or exp 'blood component'/ or exp 'blood transfusion'/ or exp 'blood clotting factors'/)).tw.

(10)

PubMed

(neonat* OR child* OR paediatric* OR pediatric* OR infant* OR pediatric*OR newborn* OR adolescent*)

AND

(“extracorporeal circulation” OR bypass OR “cardiopulmonary bypass” OR “heart bypass” OR

“heart-lung-machine” OR “cardiac surgery” OR “heart surgery” OR “heart operation”)

AND

(operativ* OR perioperativ* OR preoperativ* OR postoperativ* OR intraoperativ* OR “intensive care” OR “critical care” OR ICU OR PICU OR theatres)

AND

(hemorrhag* OR “blood loss” OR bleeding OR hematoma OR hemothorax OR coagul* OR hemostasis OR haemostasis OR fibrinolysis OR “platelet activation” OR tamponade OR

“pericardial effusion” OR thrombosis OR embolism OR thromboembolism OR “blood management” OR “blood sparing” OR “blood component” OR “red cell*” OR RBC OR erythrocyte OR “red blood cell” OR transfusion OR “need for blood” OR “whole blood” OR

“use of blood” OR transfus*) AND (treat* OR therapeut* OR therapy OR manage* OR transfus* OR drug OR threshold OR rule* OR restrict* OR practic* OR polic* OR strateg* OR guideline* OR indication* OR protocol* OR criteri* OR prevent* OR prophyla* OR pharmacol*) [all]

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Cochrane CENTRAL

#1 neonat* or child* or paediatric* or pediatric* or infant* or newborn* or adolescent* or juvenile or congenital

#2 'cardiopulmonary bypass' or 'heart bypass' or 'heart-lung-machine' or 'cardiac surgery' or 'heart operation'

#3 hemorrhag* or 'blood loss' or bleeding or coag* or clot* or hemostasis or haemostasis or transfus*

#4 treat* or therapy* or therapeutic* or manage* or transfus* or threshold or restrict* or practic* or polic* or strateg* or guideline* or indication* or protocol* or prevent* or prophyla* or 'blood sparing' or 'cell saver' or 'cell salvage' or 'blood component' or 'blood clotting factor*'

#5 #1 and #2 and #3 and #4

#6 MeSH descriptor: [Child] explode all trees

#7 MeSH descriptor: [Infant] explode all trees

#8 MeSH descriptor: [Cardiopulmonary Bypass] explode all trees

#9 MeSH descriptor: [Thoracic Surgery] explode all trees

#10 MeSH descriptor: [Hemorrhage] explode all trees

#11 MeSH descriptor: [Hemostasis] explode all trees

#12 MeSH descriptor: [Hematologic Agents] explode all trees

#13 MeSH descriptor: [Blood Component Transfusion] explode all trees

#14 MeSH descriptor: [Blood Coagulation Factors] explode all trees

#15 #1 or #6 or #7

#16 #2 or #8 or #9

#17 #3 or #10 or #11

#18 #4 or #12 or #13 or #14

#19 #15 and #16 and #17 and #1

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Electronic Supplement 2:

2.1 Summary of findings tables

Aprotinin compared with Placebo/Control in children undergoing cardiac surgery on bypass Efficacy Outcomes

Patient or population: children (0-18 yrs) with congenital heart disease undergoing cardiac surgery on cardiopulmonary bypass

Settings: international tertiary cardiac centre Intervention: use of aprotinin

Comparison: no drug or placebo (0.9% NaCl)

Outcomes Illustrative comparative risks*

(95% CI) Relative

effect (95% CI)

No of Participants

(studies)

Quality of the evidence (GRADE)

Comments

Assumed risk Corresponding risk

Placebo (0.9%saline)

or no drug

Aprotinin

Blood loss at 24 hours following administration of aprotinin vs control

the mean across the control groups ranged from 28.6 to 49.7 ml/kg per 24 hours

the mean in the intervention groups differed from the control groups +4.9 to -13.1 ml/kg per 24 hours the mean

difference across the studies was 6.45 ml/kg per 24 hours lower (95% CI -11.23, -1.66)

NA 419

participants (6 studies)

⊕⊕⊝⊝

low

further studies included in sensitivity analysis - 2 studies with incomplete, computed data (88

participants):

mean difference -4.68 ml/kg per 24 hours (CI -7.51, 1.85)

(13)

- 3 studies with 24h blood loss measured in ml/m²(123 participants):

mean difference -104.6 ml/m² per 24 hours (CI -172.56, -36.65)

Transfusion requirements at 24 hours following

administration of aprotinin vs control

ml/kg per 24 hours

the mean across the control groups ranged from

RBC

15.5 - 39 ml/kg per 24 hours

FFP

21 - 57.6 ml/kg per 24 hours

the mean in the intervention groups differed from the control groups RBC

-1.0 to -7.0 ml/kg per 24 hours mean difference across the studies 3.67 ml/kg per 24 hours lower (95% CI-6.07,- 1.27)

FFP

-5.0 to -21.1 ml/kg per 24 hours mean difference across the studies 10.57 ml/kg per 24 hours lower

NA

RBC 317 participants (4 studies)

FFP 278 participants (3 studies)

⊕⊕⊝⊝

low

⊕⊕⊝⊝

low

(14)

Surgical exploration following

administration of aprotinin vs control

within 24 hours from returning from theatre

mean baseline risk

11 %

(range 6 - 16

%)

mean risk in the intervention groups 22.9 %

(range 13.75 -32

%)

the mean risk across the studies was 11.9 % lower

RR 0.46 (95% CI 0.23, 0.94)

230 participants (2 studies)

⊕⊕⊕⊝

moderate

2 zero event trials

(15)

Aprotinin compared with Placebo/Control in children undergoing cardiac surgery on bypass Safety Outcomes

Settings: international tertiary cardiac centre Intervention: use of aprotinin

Outcomes No of Participants

(studies) Comments

Thrombosis 'no clinical evidence' (Mössinger 2003)

'no clinical evidence' (Bulutcu 2005)

'one patient from placebo group with clinical significant thrombosis on ECMO, requiring changing of the circuit'

(Williams 2008)

Renal dysfunction

urea/creatinine serum level (preop versus postop 4 hours to 5 days)

‘increase from baseline postop by 5+/-1 mg/l/24h, reverted back to baseline after 72h’ (Rupinder 2001)

‘creatinine at 24 h postop significantly different from preop values for aprotinin (P = 0.02) and placebo group (P = 0.06); reverted in both groups at 72 h postop (P>0.05); no significant difference between both groups’

(Williams 2008)

‘urea did not change significantly from preop baseline except for day 4 postop, when it was significantly greater in the placebo group compared to preop values (P = 0.04). This difference disappeared by day 5 postop;

creatinine was significantly lower than preop on postop days 3 (P = 0.01) and 4 (P = 0.001); these differences disappeared by postop day 5’ (D’Errico 1996)

outcomes too

heterogeneous and / or insufficiently reported for meta-analysis

(16)

Tranexamic acid (TXA) compared with Placebo/Control in children undergoing cardiac surgery on bypass Efficacy Outcomes

Settings: international tertiary cardiac centre Intervention: use of tranexamic acid

Outcomes Illustrative comparative risks* (95%

CI) Relative

effect (95% CI)

(studies)

Comments

Assumed risk Corresponding risk

Placebo (0.9%saline) or

no drug

TXA

Blood loss at 24 hours following use of TXA

ml/kg per 24 hours

21 to 40 ml/kg per 24 hours

the mean in the intervention groups differed from the control groups from -4.90 to -16.00 ml/kg per 24 hours

the mean difference across the studies was 9.02 ml/kg per 24 hours lower

NA 825

⊕⊕⊕⊝

moderate

(17)

(95% CI-11.26, -6.79)

Blood loss at 24 hours following use of

</= 50mg/kg TXA ml/kg per 24 hours

21 to 36 ml/kg per 24 hours

the mean in the intervention groups differed from the control groups from -6 to -16.00 ml/kg per 24 hours

(95% CI-12.68, -7.33)

NA 574

Blood loss at 24 hours following use of

> 50mg/kg TXA ml/kg per 24 hours

23.5 to 40 ml/kg per 24 hours

the mean in the intervention groups differed from the control groups from -4.90 to -8.00 ml/kg per 24 hours

(95% CI -9.58, -1.26)

NA 251

(18)

FFP

Platelets 16.4 - 20 ml/kg per 24 hours

(95% CI -8.33, -3.36) FFP

+5.74 to -8.0 ml/kg per 24 hours

mean difference across the studies 5.10 ml/kg per 24 hours lower (95% CI -7.94, -2.27)

Platelets

Platelets 530 participants (4 studies)

⊕⊕⊕⊝

moderate

⊕⊕⊕⊝

moderate

Transfusion requirements at 24 hours following use of

</= 50mg/kg TXA ml/kg per 24 hours

RBC

FFP

mean difference across the studies 5.2 ml/kg per 24 hours lower (95% CI -8.36, -2.04) FFP

5.74 to -8.0 ml/kg per 24 hours

NA

(19)

Transfusion requirements at 24 hours following use of

> 50mg/kg TXA ml/kg per 24 hours

RBC

25 - 39 ml/kg per 24 hours

FFP

21 - 26.3 ml/kg per 24 hours

-4.0 to -15.0 ml/kg per 24 hours

mean difference across the studies 7.46 ml/kg per 24 hours lower (95% CI-12.45, -2.48) FFP

mean difference across the studies 4.17 ml/kg per 24 hours lower (95% CI-10.55, -2.22)

NA

Surgical reexploration following

administration of TXA vs control within 24 hours from returning from theatre

mean baseline risk

10.1 % (range 2.5 - 16.7%)

mean risk in the intervention groups 3.4 %

(range 0 - 7.3 %) the mean risk across the studies was 6.7 % lower

RR 0.36 (95% CI 0.18, 0.72)

⊕⊕⊕⊝

moderate

(20)

Tranexamic acid (TXA) compared with Placebo/control in children undergoing cardiac surgery on bypass Safety Outcomes

Settings: international tertiary cardiac centre Intervention: use of tranexamic acid

Outcomes Relative effect

(95% CI) No of

Participants (studies)

Comments

Thrombosis ‚no clinical signs of thrombosis or thrombosis –related events’ (Reid 1997, Chauhan 2004, Bulutcu, Chauhan 2003, Patel 2017)

‘one cerebral infarction in TXA group’ (Shimizu 2011)

Renal dysfunction urea / creatinine serum level (preop versus 4 to 48 hours postop)

‘no significant differences in postop creatinine between groups’ (Muthialu 2015)

24h creatinine not significantly different between groups’

(Bulutcu 2005)

‘no significant differences in pre- and postop creatinine in both groups’ (Shimizu 2011)

postop need for dialysis

‘3 patients needing dialysis in aprotinin group versus none in TXA group’ (Muthialu 2015)

`No patient required dialysis postoperatively’ (Patel 2017)

not specified

‘no renal dysfunction observed’ (Chauhan 2004, Chauhan 2003, Reid 1997)

50 participants (1 study)

outcomes too

heterogeneous and / or insufficiently reported for meta-analysis

(21)

Neurological

dysfunction ‚no neurological dysfunction observed‘ (Chauhan 2004, Chauhan 2003)

`none suffered a seizure or other neurological event`

(Patel 2017)

Mortality ‘one death in control group’ (Bulutcu 2005)

‘4 deaths in aprotinin group, 2 in TXA group, all primarily related to pulmonary hypertension’ (Muthialu 2015)

‘none’ (Zonis 1996, Patel 2017)

(22)

Epsilon aminocaproic acid (EACA) compared with Placebo/Control in children undergoing cardiac surgery on bypass

Efficacy Outcomes

Settings: international tertiary cardiac centre Intervention: use of epsilon aminocaproic acid Comparison: no drug or placebo (0.9% NaCl)

Outcomes Illustrative comparative

risks* (95% CI) Relative effect (95% CI)

(studies)

Comments

Assumed risk

Corresponding risk

Placebo (0.9%saline)

or no drug

EACA

Blood loss at 24 hours following administration of EACA

the mean across the control groups ranged from 36 to 42.6 ml/kg per 24 hours

the mean in the intervention groups differed from the control groups from -4.00 to -18.90 ml/kg per 24 hours the mean difference across the studies was 10.52 ml/kg per 24 hours lower (95% CI -21.07, 0.03)

NA 410

⊕⊝⊝⊝

very low

(23)

Transfusion

requirements at 24 hours following administration of EACA vs control ml/kg per 24 hours

the mean across the control groups ranged from RBC 18-69.86 ml/kg per 24 hours

FFP 23.5-42.98 ml/kg per 24 hours

Platelets

the mean in the intervention groups differed from the control groups

RBC

-4.0 to - 30.83 ml/kg per 24 hours

mean difference across the studies 11.32 ml/kg per 24 hours lower (95%CI-17.89,- 4.76)

FFP

mean difference across the studies

-8.46 ml/kg per 24 hours lower (95%CI-16.16,- 0.75)

Platelets -5.0 to -15.8 ml/kg per 24 hours

NA

Platelets 410

⊕⊕⊝⊝

low

⊕⊕⊝⊝

low

⊕⊕⊝⊝

low

(24)

within 24 hours from

returning from theatre 13 % (range 10.8- 15.3 %)

4.3 %

(range 3.3-5.9

%)

the mean risk across the studies was 8.7

% lower

(95% CI 0.17, 0.63)

moderate

Epsilon-Aminocaproic Acid (EACA) compared with Placebo/Control in children undergoing cardiac surgery on bypass

Safety Outcomes

Settings: international tertiary cardiac centre Intervention: use of epsilon aminocaproic acid Comparison: no drug or placebo (0.9% NaCl)

Outcomes Relative effect

(95% CI) No of

Participants (studies)

Comments

Thrombosis ‘incidence of ST / T changes significantly reduced in intervention groups compared to control group (P<0.05); no differences in

incidence of seizure, paresis, focal neurological deficit, stroke’ ^(Sarupria

2013)

Renal dysfunction urea / creatinine serum level preop versus postop + creatinine clearance

‘no significant difference in incidence of renal risk, renal injury and renal failure observed between groups’ (Sarupria 2013)

(25)

not specified

‚no renal failure observed‘ (Chauhan 2004)

Neurological dysfunction‚no significant difference in the incidence of seizures, paresis, delirium or stroke observed between groups‘ (Sarupria 2013)

‘no neurological events observed’

(Chauhan 2004)

Mortality ‚5 deaths in intervention groups (n=78), 3 deaths in control group (n=37), no significant difference (P=0.88)’ (Sarupria 2013)

(26)

2.2 Assessment for publication bias: Funnel plot of comparison: Blood loss at 24 hours following administration of aprotinin vs control

2.3 Assessment for publication bias: Funnel plot of comparison: Blood loss at 24 hours following administration of TXA vs control