BJA
Correspondence
Declaration of interest None declared.
Funding No financial support was received for this study. P.-E. Bouet* V. Ruiz G. Legendre P. Gillard P. Descamps L. Sentilhes Angers, France *E-mail: [email protected] 1 Sentilhes L, Lasocki S, Deruelle P, Perrotin F, Goffinet F, DeneuxTharaux C. Tranexamic acid for the prevention and treatment of post-partum hemorrhage. Brit J Anaesth, in press, doi:10.1093/bja/ aeu448 2 Ducloy-Bouthors AS, Jude B, Duhamel A, et al. High-dose tranexamic acid reduces blood loss in postpartum haemorrhage. Critical Care 2011; 15: R117 3 Goffinet F, Mercier F, Teyssier V, et al. Groupe de Travail des RPC sur l’HPP. Postpartum hemorrhage: recommendations for clinical
practice by the CNGOF (December 2004). Gynecol Obstet Fertil 2005; 33: 268–74 4 Deneux-Tharaux C, Sentilhes L, Maillard F, et al. Effect of routine controlled cord traction as part of the active management of the third stage of labour on postpartum haemorrhage : multicentre randomised controlled trial (TRACOR). Br Med J 2013; 346: f1541 5 Shakur H, Elbourne D, Gulmezoglu M, et al. The WOMAN trial (World Maternal Antifibrinolytic Trial): tranexamic acid for the treatment of postpartum haemorrhage: an international randomized, doubleblind placebo controlled trial. Trials 2010; 11: 40
doi:10.1093/bja/aeu468
Problematic comparisons Editor—The article by Skhirtladze and colleagues1 requires comment. The title of the article suggests a direct comparison of the effects of albumin (HA), hydroxyethyl starch (HES) and Ringer’s lactate (RL). However, in all three groups the amount of administered non-study fluids (almost exclusively RL) within 24 h of surgery was approximately 2.5 times that of the study fluid (Table 4). Thus, strictly speaking this was a comparison of 1/3 HA+2/3 RL vs 1/3 HES+2/3 RL vs RL. Most worrisome, however, is the fact that this was not only a comparison of the effects of two colloids (HA, HES) vs a crystalloid (RL) but, in addition, a comparison of the effects of two completely unbalanced (HA, HES) solutions and a markedly hyperchloraemic (Cl- 154 mmol litre21) solution (HES) with those of a physiologically balanced, normochloraemic solution (RL). It has been known for two decades that chloride is a renal vasoconstrictor.2 Even in healthy individuals, the infusion of 2 litre of 0.9% normal saline resulted in a 40% decrease of renal blood flow velocity and renal cortical tissue perfusion.3 Implementation of a chloride- restrictive intravenous fluid administration strategy decreased the incidence of acute kidney injury (AKI) and renal replacement therapy (RRT) in critically ill patients.4 Thus, if the effects of HES (and to a certain degree that of HA) and a crystalloid per se were to be compared, hyperchloraemic normal saline would have been the methodologically appropriate crystalloid. However, in view of the known adverse effects of normal saline for volume replacement, a balanced third generation HES solution should have been used. As such solutions have been commercially available for several years, I do not understand why the authors did not use such a solution. In view of the known adverse effects of hyperchloraemic solutions for volume replacement on renal function, it is remarkable that the renal effects of the various solutions were comparable. The authors state that ‘the observed positive delta creatinine values in both colloid groups indicates that these patients were at increased risk for renal replacement therapy (RRT) and greater mortality’. For the following reasons, I consider this over-interpretation of data and speculation. (i) As the absolute serum creatinine concentrations at 48 h are nowhere provided, verification of the data is not possible; (ii) median creatinine concentrations in both colloid groups never exceeded baseline values and did not differ significantly from those of RL (Fig. 3); (iii) the indications for RRT are not
341
Downloaded from http://bja.oxfordjournals.org/ at Rudolph Matas Medical Library on January 25, 2015
any impairment of renal function, seizure, or maternal death in either group. This study did not demonstrate that high-dose TA to treat PPH≥800 ml after a vaginal delivery is associated with reduced blood loss, duration of bleeding, or need for transfusion. There is a very little reliable evidence from randomized trials about the effectiveness of TA for the treatment of PPH.1 2 5 Only one open-label randomized controlled trial (RCT) has studied this question, and it reported that high-dose TA may reduce blood loss (173 vs 221 ml; P¼0.04) in women with PPH (n¼72 in each group)2. To our knowledge, only five cases of renal impairment with acute renal cortical necrosis associated with TA have been reported in the literature.1 In our study, the only severe adverse manifestation was deep vein thrombosis, which occurred in one patient in the control group. However, we must note that we stopped administering high-dose TA in April 2013 after the publication of a French Periodic Safety Update Report (PSUR). After the implementation of the EXADELI protocol in the district for which the main reference maternity unit was the lead center for that EXADELI trial, the PSUR has alerted the healthcare providers of an abnormally high rate of cases of unexplained renal failure following severe PPH treated by, among other drugs, TA (http://spiral. univ-lyon1.fr/files_m/M11263/Files/897436_1562.pdf). The implementation of high-dose TA for treating PPH ≥800 ml was not associated with a significant reduction of blood loss. This finding, together with the PSUR alert about the possible effect of this treatment on renal function, leads us to conclude that for now, until the publication of the WOMAN trial,5 the potential harm outweighs the benefits of high-dose TA for treating PPH.
BJA
Declaration of interest None declared. H.-J. Priebe University of Freiburg, Germany E-mail: [email protected] 1 Skhirtladze K, Base EM, Lassnigg A, et al. Comparison of the effect of albumin 5%, hydroxyethyl starch 130/0.4 6%, and Ringer’s lactate on blood loss and coagulation after surgery. Br J Anaesth 2014; 112: 255–64 2 Wilcox CS. Regulation of renal blood flow by plasma chloride. J Clin Invest 1983; 71: 726–35 3 Chowdhury AH, Cox EF, Francis ST, Lobo DN. A randomized, controlled, double-blind crossover study on the effects of 2-L infusions of 0.9% saline and Plasma-Lyte(R) 148 on renal blood flow velocity and renal cortical tissue perfusion in healthy volunteers. Ann Surg 2012; 256: 18 –24 4 Yunos NM, Bellomo R, Hegarty C, Story D, Ho L, Bailey M. Association between a chloride-liberal vs chloride-restrictive intravenous fluid administration strategy and kidney injury in critically ill adults. JAMA 2012; 308: 1566– 72 5 Martin C, Jacob M, Vicaut E, Guidet B, Van Aken H, Kurz A. Effect of waxy maize-derived hydroxyethyl starch 130/0.4 on renal function in surgical patients. Anesthesiology 2013; 118: 387–94 6 Gillies MA, Habicher M, Jhanji S, et al. Sander M, Mythen M, Hamilton M, Pearse RM. Incidence of postoperative death and acute kidney injury associated with i.v. 6% hydroxyethyl starch use: systematic review and meta-analysis. Br J Anaesth 2014; 112: 25 –34
342
7 Van Der Linden P, James M, Mythen M, Weiskopf RB. Safety of modern starches used during surgery. Anesth Analg 2013; 116: 35 –48
doi:10.1093/bja/aeu469
Comparison of the effects of albumin 5%, hydroxyethyl starch 130/0.4 6%, and Ringer’s lactate: Reply to Prof Priebe Reply from the authors Editor—We thank Prof. Priebe for his critical comments on our article.1 Prof. Priebe is concerned that the title we used would be misleading as there was no direct comparison between the three solutions but between two colloids plus additional Ringer’s lactate and Ringer’s lactate alone. Although not explicitly mentioned in the title this procedural method is clearly stated in the Methods section under ‘Randomization, fluid regimen and blinding’. Because of the known upper limit regarding the daily dosage of hydroxyethylstarch 130/0.4 it should be evident to the reader that the total fluid intake in the hydroxyethylstarch 130/0.4 group cannot be achieved by administering solely study solution. Instead of comparing physiologically more identical solutions our approach was rather a pragmatic one as 5% human albumin, 6% hydroxyethylstarch 130/0.4 and Ringer’s lactate are frequently employed worldwide for this purpose. We do agree that it would have been more opportune to use a balanced hydroxyethylstarch solution as compared with the unbalanced solution we used, which contains a high concentration of chloride. The reason for our choice was again an overall more frequent use of unbalanced hydroxyethylstarch 130/0.4 in those days. In fact, an equivalence study, comparing balanced and unbalanced hydroxyethylstarch 130/0.4 had previously been performed at our institution.2 Prof. Priebe lists all the negative effects of a high chloride intake pertaining to renal function. However, he subsequently doubts that any harm was done to our patients who had received unbalanced hydroxyethylstarch 130/0.4. The positive delta creatinine values we observed in both colloid groups, is deemed being ‘clinically irrelevant’. In contrast to this opinion, Lassnigg and colleagues3 found a significant association between mortality after cardiac surgery and even minimal increases in serum creatinine postoperatively. In this context, we would further like to emphasize that the main outcome variable was not postoperative kidney function but blood loss over the first 24 h after cardiopulmonary bypass. Accordingly, the study was not powered to provide significant differences between study solutions as to renal replacement therapy and mortality although the number of patients included in this single-centre study is higher than in any previously published trial on this topic.4 As mentioned above, our study used postoperative blood loss as the primary outcome variable and it has been clearly stated that bleeding as well as chest tube drainage was not different between the groups. Yet, our findings also revealed that the transfusion trigger was reached earlier in the colloid groups
Downloaded from http://bja.oxfordjournals.org/ at Rudolph Matas Medical Library on January 25, 2015
specified. In any case, median increases in creatinine concentrations of 0.06 and 0.02 mg dl21 in the HA and HES groups, respectively, are clinically irrelevant. Apart from these major limitations, there are additional issues. (i) The findings apply to a highly selected population. Of initially 2548 screened patients, only 240 (,10%) were included in the study. (ii) This is a study of non-consecutive patients. For? ‘logistic’ reasons, 620 patients (24%) were not included. The definition of logistic reason is not provided. The exact time period during which the study was performed is not specified. (iii) An a priori power calculation indicated that 80 patients per group were required. In fact, the HA and RL groups consisted of only 76 and 79 patients, respectively. Strictly speaking, the study is underpowered. (iv) Fluid administration was not goal-directed. Although the ‘impact of fluid loading’ on myocardial performance was monitored by transoesophageal echocardiography, fluids were administered ‘as required’ and ‘at the discretion of the attending consultant and not controlled by protocol’. (v) Decisions on the administration of fresh frozen plasma and platelets were based on thromboelastography, a purely ex vivo coagulation test which does not necessarily reflect clinical bleeding. Several recent meta-analyses (including several investigations in cardiac surgery patients) did not find any association between HES containing solutions and renal dysfunction,5 – 7 increased blood loss7 and allogeneic erythrocyte transfusion7 in surgical patients. In view of the numerous considerable methodological problems, the validity of the findings by Skhirtladze and colleagues1 is questionable.
Correspondence
Correspondence
Declaration of interest None declared.
Funding No financial support was received for this study. P.-E. Bouet* V. Ruiz G. Legendre P. Gillard P. Descamps L. Sentilhes Angers, France *E-mail: [email protected] 1 Sentilhes L, Lasocki S, Deruelle P, Perrotin F, Goffinet F, DeneuxTharaux C. Tranexamic acid for the prevention and treatment of post-partum hemorrhage. Brit J Anaesth, in press, doi:10.1093/bja/ aeu448 2 Ducloy-Bouthors AS, Jude B, Duhamel A, et al. High-dose tranexamic acid reduces blood loss in postpartum haemorrhage. Critical Care 2011; 15: R117 3 Goffinet F, Mercier F, Teyssier V, et al. Groupe de Travail des RPC sur l’HPP. Postpartum hemorrhage: recommendations for clinical
practice by the CNGOF (December 2004). Gynecol Obstet Fertil 2005; 33: 268–74 4 Deneux-Tharaux C, Sentilhes L, Maillard F, et al. Effect of routine controlled cord traction as part of the active management of the third stage of labour on postpartum haemorrhage : multicentre randomised controlled trial (TRACOR). Br Med J 2013; 346: f1541 5 Shakur H, Elbourne D, Gulmezoglu M, et al. The WOMAN trial (World Maternal Antifibrinolytic Trial): tranexamic acid for the treatment of postpartum haemorrhage: an international randomized, doubleblind placebo controlled trial. Trials 2010; 11: 40
doi:10.1093/bja/aeu468
Problematic comparisons Editor—The article by Skhirtladze and colleagues1 requires comment. The title of the article suggests a direct comparison of the effects of albumin (HA), hydroxyethyl starch (HES) and Ringer’s lactate (RL). However, in all three groups the amount of administered non-study fluids (almost exclusively RL) within 24 h of surgery was approximately 2.5 times that of the study fluid (Table 4). Thus, strictly speaking this was a comparison of 1/3 HA+2/3 RL vs 1/3 HES+2/3 RL vs RL. Most worrisome, however, is the fact that this was not only a comparison of the effects of two colloids (HA, HES) vs a crystalloid (RL) but, in addition, a comparison of the effects of two completely unbalanced (HA, HES) solutions and a markedly hyperchloraemic (Cl- 154 mmol litre21) solution (HES) with those of a physiologically balanced, normochloraemic solution (RL). It has been known for two decades that chloride is a renal vasoconstrictor.2 Even in healthy individuals, the infusion of 2 litre of 0.9% normal saline resulted in a 40% decrease of renal blood flow velocity and renal cortical tissue perfusion.3 Implementation of a chloride- restrictive intravenous fluid administration strategy decreased the incidence of acute kidney injury (AKI) and renal replacement therapy (RRT) in critically ill patients.4 Thus, if the effects of HES (and to a certain degree that of HA) and a crystalloid per se were to be compared, hyperchloraemic normal saline would have been the methodologically appropriate crystalloid. However, in view of the known adverse effects of normal saline for volume replacement, a balanced third generation HES solution should have been used. As such solutions have been commercially available for several years, I do not understand why the authors did not use such a solution. In view of the known adverse effects of hyperchloraemic solutions for volume replacement on renal function, it is remarkable that the renal effects of the various solutions were comparable. The authors state that ‘the observed positive delta creatinine values in both colloid groups indicates that these patients were at increased risk for renal replacement therapy (RRT) and greater mortality’. For the following reasons, I consider this over-interpretation of data and speculation. (i) As the absolute serum creatinine concentrations at 48 h are nowhere provided, verification of the data is not possible; (ii) median creatinine concentrations in both colloid groups never exceeded baseline values and did not differ significantly from those of RL (Fig. 3); (iii) the indications for RRT are not
341
Downloaded from http://bja.oxfordjournals.org/ at Rudolph Matas Medical Library on January 25, 2015
any impairment of renal function, seizure, or maternal death in either group. This study did not demonstrate that high-dose TA to treat PPH≥800 ml after a vaginal delivery is associated with reduced blood loss, duration of bleeding, or need for transfusion. There is a very little reliable evidence from randomized trials about the effectiveness of TA for the treatment of PPH.1 2 5 Only one open-label randomized controlled trial (RCT) has studied this question, and it reported that high-dose TA may reduce blood loss (173 vs 221 ml; P¼0.04) in women with PPH (n¼72 in each group)2. To our knowledge, only five cases of renal impairment with acute renal cortical necrosis associated with TA have been reported in the literature.1 In our study, the only severe adverse manifestation was deep vein thrombosis, which occurred in one patient in the control group. However, we must note that we stopped administering high-dose TA in April 2013 after the publication of a French Periodic Safety Update Report (PSUR). After the implementation of the EXADELI protocol in the district for which the main reference maternity unit was the lead center for that EXADELI trial, the PSUR has alerted the healthcare providers of an abnormally high rate of cases of unexplained renal failure following severe PPH treated by, among other drugs, TA (http://spiral. univ-lyon1.fr/files_m/M11263/Files/897436_1562.pdf). The implementation of high-dose TA for treating PPH ≥800 ml was not associated with a significant reduction of blood loss. This finding, together with the PSUR alert about the possible effect of this treatment on renal function, leads us to conclude that for now, until the publication of the WOMAN trial,5 the potential harm outweighs the benefits of high-dose TA for treating PPH.
BJA
Declaration of interest None declared. H.-J. Priebe University of Freiburg, Germany E-mail: [email protected] 1 Skhirtladze K, Base EM, Lassnigg A, et al. Comparison of the effect of albumin 5%, hydroxyethyl starch 130/0.4 6%, and Ringer’s lactate on blood loss and coagulation after surgery. Br J Anaesth 2014; 112: 255–64 2 Wilcox CS. Regulation of renal blood flow by plasma chloride. J Clin Invest 1983; 71: 726–35 3 Chowdhury AH, Cox EF, Francis ST, Lobo DN. A randomized, controlled, double-blind crossover study on the effects of 2-L infusions of 0.9% saline and Plasma-Lyte(R) 148 on renal blood flow velocity and renal cortical tissue perfusion in healthy volunteers. Ann Surg 2012; 256: 18 –24 4 Yunos NM, Bellomo R, Hegarty C, Story D, Ho L, Bailey M. Association between a chloride-liberal vs chloride-restrictive intravenous fluid administration strategy and kidney injury in critically ill adults. JAMA 2012; 308: 1566– 72 5 Martin C, Jacob M, Vicaut E, Guidet B, Van Aken H, Kurz A. Effect of waxy maize-derived hydroxyethyl starch 130/0.4 on renal function in surgical patients. Anesthesiology 2013; 118: 387–94 6 Gillies MA, Habicher M, Jhanji S, et al. Sander M, Mythen M, Hamilton M, Pearse RM. Incidence of postoperative death and acute kidney injury associated with i.v. 6% hydroxyethyl starch use: systematic review and meta-analysis. Br J Anaesth 2014; 112: 25 –34
342
7 Van Der Linden P, James M, Mythen M, Weiskopf RB. Safety of modern starches used during surgery. Anesth Analg 2013; 116: 35 –48
doi:10.1093/bja/aeu469
Comparison of the effects of albumin 5%, hydroxyethyl starch 130/0.4 6%, and Ringer’s lactate: Reply to Prof Priebe Reply from the authors Editor—We thank Prof. Priebe for his critical comments on our article.1 Prof. Priebe is concerned that the title we used would be misleading as there was no direct comparison between the three solutions but between two colloids plus additional Ringer’s lactate and Ringer’s lactate alone. Although not explicitly mentioned in the title this procedural method is clearly stated in the Methods section under ‘Randomization, fluid regimen and blinding’. Because of the known upper limit regarding the daily dosage of hydroxyethylstarch 130/0.4 it should be evident to the reader that the total fluid intake in the hydroxyethylstarch 130/0.4 group cannot be achieved by administering solely study solution. Instead of comparing physiologically more identical solutions our approach was rather a pragmatic one as 5% human albumin, 6% hydroxyethylstarch 130/0.4 and Ringer’s lactate are frequently employed worldwide for this purpose. We do agree that it would have been more opportune to use a balanced hydroxyethylstarch solution as compared with the unbalanced solution we used, which contains a high concentration of chloride. The reason for our choice was again an overall more frequent use of unbalanced hydroxyethylstarch 130/0.4 in those days. In fact, an equivalence study, comparing balanced and unbalanced hydroxyethylstarch 130/0.4 had previously been performed at our institution.2 Prof. Priebe lists all the negative effects of a high chloride intake pertaining to renal function. However, he subsequently doubts that any harm was done to our patients who had received unbalanced hydroxyethylstarch 130/0.4. The positive delta creatinine values we observed in both colloid groups, is deemed being ‘clinically irrelevant’. In contrast to this opinion, Lassnigg and colleagues3 found a significant association between mortality after cardiac surgery and even minimal increases in serum creatinine postoperatively. In this context, we would further like to emphasize that the main outcome variable was not postoperative kidney function but blood loss over the first 24 h after cardiopulmonary bypass. Accordingly, the study was not powered to provide significant differences between study solutions as to renal replacement therapy and mortality although the number of patients included in this single-centre study is higher than in any previously published trial on this topic.4 As mentioned above, our study used postoperative blood loss as the primary outcome variable and it has been clearly stated that bleeding as well as chest tube drainage was not different between the groups. Yet, our findings also revealed that the transfusion trigger was reached earlier in the colloid groups
Downloaded from http://bja.oxfordjournals.org/ at Rudolph Matas Medical Library on January 25, 2015
specified. In any case, median increases in creatinine concentrations of 0.06 and 0.02 mg dl21 in the HA and HES groups, respectively, are clinically irrelevant. Apart from these major limitations, there are additional issues. (i) The findings apply to a highly selected population. Of initially 2548 screened patients, only 240 (,10%) were included in the study. (ii) This is a study of non-consecutive patients. For? ‘logistic’ reasons, 620 patients (24%) were not included. The definition of logistic reason is not provided. The exact time period during which the study was performed is not specified. (iii) An a priori power calculation indicated that 80 patients per group were required. In fact, the HA and RL groups consisted of only 76 and 79 patients, respectively. Strictly speaking, the study is underpowered. (iv) Fluid administration was not goal-directed. Although the ‘impact of fluid loading’ on myocardial performance was monitored by transoesophageal echocardiography, fluids were administered ‘as required’ and ‘at the discretion of the attending consultant and not controlled by protocol’. (v) Decisions on the administration of fresh frozen plasma and platelets were based on thromboelastography, a purely ex vivo coagulation test which does not necessarily reflect clinical bleeding. Several recent meta-analyses (including several investigations in cardiac surgery patients) did not find any association between HES containing solutions and renal dysfunction,5 – 7 increased blood loss7 and allogeneic erythrocyte transfusion7 in surgical patients. In view of the numerous considerable methodological problems, the validity of the findings by Skhirtladze and colleagues1 is questionable.
Correspondence
