Overall, 267 patients received HES and 263 patients received another colloid or a crystalloid solution.
Peri-operative overall fluid administration was not significantly different between HES and other solutions [N=6 studies, mean difference 0.04; 95% CI (−1.76 to 1.84) ml kg−1, I2 = 78%, P of I2 = 0.0005] (Fig. 1a). Intra-operative administration of vasoactive drugs and postoperative Hb concentration on day 1 were also not significantly different between HES and other fluids [N=2 studies, risk ratio = 1.53 (0.61 to 3.81), I2 = 0%, P of I2 = 0.59; N=2 studies, mean difference 0.04; 95% CI (−0.63 to 0.71) g dl−1, I2 = 0%, P of I2 = 0.57] (Fig. 1b and c, respectively).
Regarding the effects of HES on renal function, there was no difference in peri-operative urine output when comparing HES and other fluids [N=4 studies, mean difference −7.17; 95% CI (−17.29 to 2.95) ml, I2 = 57%, P of I2 = 0.07] (Fig. 2a). Postoperative creatinine levels on day 1 were not significantly different between HES and control groups [N=2 studies, mean difference −2.07; 95% CI (−4.92 to 0.78) mg ml−1, I2 = 0%, P of I2 = 0.86] (Fig. 2b).
Regarding the effects of HES on coagulation function, there was no significant effect of HES on peri-operative blood loss on day 1 [N=5 studies, mean difference −0.01; 95% CI (−0.22 to 0.24) ml kg−1; I2 = 0%, P of I2 = 0.7] (Fig. 3a). The volume of red blood cells and fresh frozen plasma transfused on day 1 was similar between HES and other fluids [N=4 studies mean difference −2.23; 95% CI (−3.31 to 2.85) ml kg−1, I2 = 0%, P of I2 = 0.9: N=5 studies; mean difference 0.01; 95% CI (−2.10 to 2.13) ml kg−1, I2 = 0%, P of I2 = 0.66, respectively] (Fig. 3b and c). Coagulation markers (activated partial prothombrin time and fibrinogen) on day 1 were not significantly different between HES and other fluids [N=3 studies, mean difference −0.79; 95% CI (−2.97 to 1.39), I2 = 38%, P of I2 = 0.2; N=2 studies, mean difference −0.22; 95% CI (−0.48 to 0.05), I2 = 48%, P of I2 = 0.17].
Finally, knowing that our meta-analysis was the first performed on this specific topic, no correction for the alpha risk was required.
One study was suspected of misconduct given that the first author has already retracted many studies on the same topic.29 Removing this study from the analysis did not significantly modify the results: postoperative overall fluid administration [N=5 studies, mean difference −0.7; 95% CI (−2.45 to 1.05) ml kg−1, I2 = 69%, P of I2 = 0.01], urine output on day 1 [N=3 studies, mean difference −2.01; 95% CI (−7.05 to 3.03) ml kg−1, I2 = 0%, P of I2 = 0.81], postoperative creatinine concentration on day 1 [N=1 study, mean difference −3; 95% CI (−13.89 to 7.89)] and blood loss on day 1 [N=4 studies, mean difference 0; 95% CI (−0.23 to 0.24) ml kg−1; I2 = 0%, P of I2 = 0.40].
Subgroup analyses displayed similar results to the overall results except for the total fluid intakes on day 1, which were significantly less in the subgroup of studies performed in noncardiac surgery (Table 2).
In accordance with GRADE recommendations, the following adjustments were performed: one level downgraded for bias of included studies (considered as serious), one level downgraded for inconsistency of results (considered as serious: because of heterogeneity of results or the random effect model used) and one level downgraded for lack of power of the analysis concerning the primary outcome.44,45,53–59 Consequently, all primary outcomes of this meta-analysis were graded as ‘very low level of evidence’ (Supplementary file 2, http://links.lww.com/EJA/A140).
The current first meta-analysis on the effects of peri-operative HES in children undergoing both cardiac and noncardiac surgery did not find any significant difference between HES and control solutions for the following outcomes: the decrease of amount of intravenously administered solutions, renal function, coagulation function and blood loss. In a subgroup analysis of patients undergoing noncardiac surgery, the efficacy of HES was found to be slightly superior to control solutions given that the total amount of fluid was significantly decreased when using HES. However, the current meta-analysis lacked power to show any difference (as suggested by trial sequential analyses) and the level of evidence grades were very low.
In adult patients, it is now clear that HES should not be used in septic patients. Evidence against their use during the peri-operative period is less strong.25,60–64 In addition, meta-analyses performed on adult studies did not show any significant differences between HES and other fluids. However, the heterogeneity of results, the lack of good quality studies and the lack of power (as suggested by trial sequential analyses) of these meta-analyses clearly impair their level of evidence. As a result, no clear conclusions can be drawn concerning the safety of HES.27,28 Regarding critically ill children, apart from platelet count and duration of ICU stay, no adverse effects of HES have been described and, in particular, no renal impairment.38,65 However, one of these two reviews focused on exotic clinical situations where studies were performed during dengue shock syndrome and severe malaria, which clearly limit their generalisation to the peri-operative period. The second meta-analysis, more close to ours from a clinical point of view, nevertheless included patients following cardiac surgery, that is a more restrictive clinical situation with consequently fewer patients than in the current review.66–70
During the peri-operative period, our meta-analysis showed that HES was associated neither with significant reductions in urine output nor with significant increases in serum creatinine levels. This result is in accordance with conclusions of a previous meta-analysis in paediatric patients.65 However, given the wide CIs of results, the small sample size and the low level of evidence, our study cannot definitively conclude regarding potential renal adverse effect in paediatric patients. Considering these limitations and the strong evidence of an association between HES use and an increased incidence of acute kidney injury in adult patients,7,71,72 it appears reasonable to suggest that HES should not be used in paediatric patients with pre-existing renal dysfunction.
Our meta-analysis did not show any significant difference in effect between HES and other fluids on blood platelet counts or coagulation test results in surgical paediatric patients. Moreover, bleeding was similar between patients receiving HES and those receiving other solutions. This result was different to the meta-analysis performed by Li et al.65 who reported decreased platelet counts in critically care patients. Although, many studies have not observed any significant change in prothrombin time and APTT following HES administration in paediatric patients,33,34,73 Haas et al.32 reported impairment in thrombelastometric parameters and global coagulation tests following HES administration in comparison with albumin or gelatin solutions. Moreover, Miller et al.74 also reported increased blood loss associated with the use of HES after cardiopulmonary bypass in paediatric patients. There is a strong association between coagulation disorders and peri-operative bleeding, especially during cardiac surgery.75,76 Summarising our results and the available literature, a detrimental effect of HES on haemostasis could not be excluded, especially during cardiac surgery.
Despite the potential adverse effects of HES, one should be aware that crystalloids have adverse effects.77–81 The use of 0.9% saline is associated with hyperchloraemic metabolic acidosis and renal dysfunction, and hyperchloraemia is independently associated with increased mortality after noncardiac surgery.81 Therefore, physicians should be aware that all intravenous fluids should be considered medicines capable of producing adverse effects, especially if recommended indications, contraindications and maximum dosages are not respected.
The beneficial effects of HES are poorly documented in the current study. However, subgroup analysis found a slight but significant decrease in the total volume of peri-operative fluids administered in children receiving HES during noncardiac surgery. This result should be interpreted in the light of previous studies with comparable outcomes. Many trials have demonstrated improvements in urine output, increases in left ventricular ejection fraction, lower requirements for vasopressors, as well as a better fluid balance pattern with a reduced risk of fluid overload and an improvement in liver perfusion, when comparing HES with crystalloids,78–80 and some of the trials include paediatric patients. Thus, more studies are needed to explore the benefits of using HES in children, especially in noncardiac surgery.
Our meta-analysis also shows that there was no significant difference between HES and human albumin, regarding efficacy or side-effects. The lack of proven superiority of human albumin over HES, its high cost and the potential risk of contamination by an unconventional transmissible agent make the routine administration of human albumin for vascular loading highly questionable in the peri-operative period in children.
There are several limitations to this meta-analysis and caution must be used in the interpretation of the results. First, the analysis is based on only nine RCTs and some of them included a relatively small sample size of paediatric patients. One study by Haas et al.32 was excluded because of the use of interquartile range, which cannot be correctly included in meta-analyses. Second, control groups in the included studies used a variety of fluids including fresh frozen plasma, human albumin, gelatin and crystalloids. However, subgroup analyses (Table 2) were performed according to the specific fluid used in the control group to investigate effects of this factor on results (with unchanged conclusions in comparison with overall results). Third, there was substantial heterogeneity in included studies, including in patient characteristics (e.g. age and other baseline data), which may have affected results. Fourth, one study performed by Boldt was included in analyses given the absence of retraction of this work from valid literature. Of note, a previous meta-analysis performed by Zarychanski et al. found Boldt's studies to influence overall results.48,82 Consequently, sensitivity analyses were performed to assess the impact of this study on overall results of our meta-analysis. Although, the study performed by Boldt did not impact the directness of our results, overall quantitative effects might have been impacted by including this effect. Fifth, renal function was assessed using poorly sensitive renal biomarkers, such as urine output or plasma creatinine levels. There was an insufficient number of studies assessing renal function with more accurate and sensitive renal biomarkers, such as α-1-microglobulin, N-acetyl-β-d-glucosaminidase or neutrophil gelatinase-associated lipocalin. However, a recent systematic review reported that there is currently no indication in the literature that the use of tetrastarches induces adverse renal effects in surgical adult patients.39
The current meta-analysis, with its included efficacy and various safety analyses, demonstrates no relevant differences between HES and control fluid groups. There was no significant increased renal toxicity of HES compared with other solutions, during both cardiac and noncardiac surgery in children. The relatively small number of studies (and numbers of patients within these included studies), the high heterogeneity of results, the lack of power of this meta-analysis and the very low grade of evidence preclude any firm conclusions regarding safety and efficacy. As a consequence, paediatric anaesthesiologists are urged to perform more studies to elucidate the role of HES in the peri-operative paediatric patient population.
Assistance with the study: none.
Financial support and sponsorship: none.
Conflicts of interest: none.
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