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. E. Base* M. Dworschak K. Skhirtladze-Dworschak A. Lassnigg Vienna, Austria *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 Base EM, Standl T, Lassnigg A, et al. Efficacy and safety of hydroxyethyl starch 6% 130/0.4 in a balanced electrolyte solution (Volulyte) during cardiac surgery. J Cardiothorac Vasc Anesth 2011; 25: 407–14 3 Lassnigg A, Schmid ER, Hiesmayr M, et al. Impact of minimal increases in serum creatinine on outcome in patients after cardiothoracic surgery: do we have to revise current definitions of acute renal failure? Crit Care Med 2008; 36: 1129–37 4 Van Der Linden P, James M, Mythen M, Weiskopf RB. Safety of modern starches used during surgery. Anesth Analg 2013; 116: 35 –48 5 Kasper SM, Meinert P, Kampe S, et al. Large-dose hydroxyethyl starch 130/0.4 does not increase blood loss and transfusion requirements
in coronary artery bypass surgery compared with hydroxyethyl starch 200/0.5 at recommended doses. Anesthesiology 2003; 99: 42 – 7 6 Lee JS, Ahn SW, Song JW, Shim JK, Yoo KJ, Kwak YL. Effect of hydroxyethyl starch 130/0.4 on blood loss and coagulation in patients with recent exposure to dual antiplatelet therapy undergoing off-pump coronary artery bypass graft surgery. Circ J 2011; 75: 2397– 402 7 Van der Linden PJ, De Hert SG, Deraedt D, et al. Hydroxyethyl starch 130/0.4 versus modified fluid gelatin for volume expansion in cardiac surgery patients: the effects on perioperative bleeding and transfusion needs. Anesth Analg 2005; 101: 629– 34 8 Enriquez LJ, Shore-Lesserson L. Point-of-care coagulation testing and transfusion algorithms. Br J Anaesth 2009; 103(Suppl 1): i14– 22
doi:10.1093/bja/aeu470
Depth of anaesthesia optimisation and postoperative cognitive dysfunction Editor—We were very interested to read the excellent review in the March issue of the British Journal of Anaesthesia entitled ‘Perioperative cognitive trajectory in adults’.1 However, we feel that the overall impression that anaesthetists may gain from reading this review will be that anaesthesia is an unimportant component in the production of postoperative cognitive dysfunction (POCD). While pre-existing trajectories of cognitive decline are undoubtedly important in predicting a patient’s fate from anaesthesia and surgery in this regard, we think it would be wrong to suggest that ‘any old anaesthetic’ will do, particularly for our elderly population. We agree with the authors that when anaesthesia is optimised and surgery is successful, patients may not suffer significant, long-term cognitive decline and may indeed expect to have some degree of cognitive improvement. However, how do we know that anaesthesia is optimised in a particular patient unless we measure overall oxygen delivery, and in particular what is going on in the brain?2 The authors allude to this possibility when they mention a randomised controlled trial (RCT) carried out in our own unit using cerebral oxygenation and ‘depth of anaesthesia’ or, better, degree of cortical suppression optimised to a range where neurotoxicity would be minimised and neural protection maximised.3 However, one of the largest proof-of-concept RCTs investigating depth of anaesthesia monitoring and POCD was not mentioned. This was the Cognitive Dysfunction after Anaesthesia (CODA) trial from Hong Kong, where more than 900 elderly patients were randomised to an intervention that maintained the bispectral index (BIS) in the 40 –60 range vs a control group where anaesthesia was administered as usual.4 The important point about this trial is that the investigators were able to maintain an average BIS (Covidien, USA) of 53 in the intervention group vs 36 in the control group. This not only resulted in a significant decrease in POCD, but also in postoperative delirium, which we acknowledge is a cause of significant postoperative morbidity. Interestingly, another even larger RCT using BIS from Berlin showed a reduction in postoperative delirium but not POCD. This was possibly due to the fact that the overall average BIS
343
Downloaded from http://bja.oxfordjournals.org/ at Rudolph Matas Medical Library on January 25, 2015
resulting in a higher transfusion rate in each of these two groups. Therefore, our study is well in line with others demonstrating no increased blood loss with the use of hydroxyethyl starches but increased transfusion rates in patients treated with starches when compared with electrolyte solutions.4 It is correct that fluid administration in our trial did not follow a goal directed therapy protocol. It rather relied on the subjective treatment options of experienced staff anaesthesiologists. The decision to not consider a goal directed therapy protocol for patient management was based on two reasons: first, changes in preload, afterload and contractility occur rapidly particularly when going off bypass. This greatly impedes the applicability of a strict goal directed protocol. Secondly, at present, there is no consensus on a clinically robust haemodynamic or metabolic variable that clearly defines adequate volume therapy during frequently changing haemodynamic conditions. This may also be the reason why other researchers refrained from using a strict goal directed fluid regimen, too.5 – 7 One can argue whether thromboelastography is the ideal foundation to guide transfusion of fresh frozen plasma and platelets. Nevertheless, it is frequently employed in cardiac surgery as a simple point-of-care test that provides important information on blood coagulation. Moreover, transfusion algorithms based on thromboelastography have been shown to reduce both transfusion requirements and blood loss in cardiac surgery.8 Logistic reasons have not specifically been mentioned in our article. They comprise the usual obstacles we face in our daily work like: ICU beds not being available for recruited patients, changes in the booking of enrolled patients, and availability of staff involved in the study.
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. E. Base* M. Dworschak K. Skhirtladze-Dworschak A. Lassnigg Vienna, Austria *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 Base EM, Standl T, Lassnigg A, et al. Efficacy and safety of hydroxyethyl starch 6% 130/0.4 in a balanced electrolyte solution (Volulyte) during cardiac surgery. J Cardiothorac Vasc Anesth 2011; 25: 407–14 3 Lassnigg A, Schmid ER, Hiesmayr M, et al. Impact of minimal increases in serum creatinine on outcome in patients after cardiothoracic surgery: do we have to revise current definitions of acute renal failure? Crit Care Med 2008; 36: 1129–37 4 Van Der Linden P, James M, Mythen M, Weiskopf RB. Safety of modern starches used during surgery. Anesth Analg 2013; 116: 35 –48 5 Kasper SM, Meinert P, Kampe S, et al. Large-dose hydroxyethyl starch 130/0.4 does not increase blood loss and transfusion requirements
in coronary artery bypass surgery compared with hydroxyethyl starch 200/0.5 at recommended doses. Anesthesiology 2003; 99: 42 – 7 6 Lee JS, Ahn SW, Song JW, Shim JK, Yoo KJ, Kwak YL. Effect of hydroxyethyl starch 130/0.4 on blood loss and coagulation in patients with recent exposure to dual antiplatelet therapy undergoing off-pump coronary artery bypass graft surgery. Circ J 2011; 75: 2397– 402 7 Van der Linden PJ, De Hert SG, Deraedt D, et al. Hydroxyethyl starch 130/0.4 versus modified fluid gelatin for volume expansion in cardiac surgery patients: the effects on perioperative bleeding and transfusion needs. Anesth Analg 2005; 101: 629– 34 8 Enriquez LJ, Shore-Lesserson L. Point-of-care coagulation testing and transfusion algorithms. Br J Anaesth 2009; 103(Suppl 1): i14– 22
doi:10.1093/bja/aeu470
Depth of anaesthesia optimisation and postoperative cognitive dysfunction Editor—We were very interested to read the excellent review in the March issue of the British Journal of Anaesthesia entitled ‘Perioperative cognitive trajectory in adults’.1 However, we feel that the overall impression that anaesthetists may gain from reading this review will be that anaesthesia is an unimportant component in the production of postoperative cognitive dysfunction (POCD). While pre-existing trajectories of cognitive decline are undoubtedly important in predicting a patient’s fate from anaesthesia and surgery in this regard, we think it would be wrong to suggest that ‘any old anaesthetic’ will do, particularly for our elderly population. We agree with the authors that when anaesthesia is optimised and surgery is successful, patients may not suffer significant, long-term cognitive decline and may indeed expect to have some degree of cognitive improvement. However, how do we know that anaesthesia is optimised in a particular patient unless we measure overall oxygen delivery, and in particular what is going on in the brain?2 The authors allude to this possibility when they mention a randomised controlled trial (RCT) carried out in our own unit using cerebral oxygenation and ‘depth of anaesthesia’ or, better, degree of cortical suppression optimised to a range where neurotoxicity would be minimised and neural protection maximised.3 However, one of the largest proof-of-concept RCTs investigating depth of anaesthesia monitoring and POCD was not mentioned. This was the Cognitive Dysfunction after Anaesthesia (CODA) trial from Hong Kong, where more than 900 elderly patients were randomised to an intervention that maintained the bispectral index (BIS) in the 40 –60 range vs a control group where anaesthesia was administered as usual.4 The important point about this trial is that the investigators were able to maintain an average BIS (Covidien, USA) of 53 in the intervention group vs 36 in the control group. This not only resulted in a significant decrease in POCD, but also in postoperative delirium, which we acknowledge is a cause of significant postoperative morbidity. Interestingly, another even larger RCT using BIS from Berlin showed a reduction in postoperative delirium but not POCD. This was possibly due to the fact that the overall average BIS
343
Downloaded from http://bja.oxfordjournals.org/ at Rudolph Matas Medical Library on January 25, 2015
resulting in a higher transfusion rate in each of these two groups. Therefore, our study is well in line with others demonstrating no increased blood loss with the use of hydroxyethyl starches but increased transfusion rates in patients treated with starches when compared with electrolyte solutions.4 It is correct that fluid administration in our trial did not follow a goal directed therapy protocol. It rather relied on the subjective treatment options of experienced staff anaesthesiologists. The decision to not consider a goal directed therapy protocol for patient management was based on two reasons: first, changes in preload, afterload and contractility occur rapidly particularly when going off bypass. This greatly impedes the applicability of a strict goal directed protocol. Secondly, at present, there is no consensus on a clinically robust haemodynamic or metabolic variable that clearly defines adequate volume therapy during frequently changing haemodynamic conditions. This may also be the reason why other researchers refrained from using a strict goal directed fluid regimen, too.5 – 7 One can argue whether thromboelastography is the ideal foundation to guide transfusion of fresh frozen plasma and platelets. Nevertheless, it is frequently employed in cardiac surgery as a simple point-of-care test that provides important information on blood coagulation. Moreover, transfusion algorithms based on thromboelastography have been shown to reduce both transfusion requirements and blood loss in cardiac surgery.8 Logistic reasons have not specifically been mentioned in our article. They comprise the usual obstacles we face in our daily work like: ICU beds not being available for recruited patients, changes in the booking of enrolled patients, and availability of staff involved in the study.
BJA
