- Email: [email protected]
Clinical outcome benefits of pretreatment with levosimendan
Correspondence
Mr I. Mulcahy, National Joint Registry). As NAP3’s denominator also included Scotland and Northern Ireland, the denominator will considerably exceed 100 000 operations. Although the NJR data do not allow us to state, with confidence, how many of these operations were performed under CNB, nor how many under epidural, we can state that only one of the 50 adult perioperative nonobstetric cases reviewed by NAP3 (including those later excluded on the grounds of date of CNB or hospital funding) was a lower limb arthroplasty, in which epidural anaesthesia was the CNB. Of these 50 cases, 13 underwent orthopaedic surgery including eight primary joint replacements and two revision joint replacements. Six spinals and two combined spinal–epidurals (CSEs) were used for primary arthroplasty and one CSE and one epidural for the revision arthroplasties. Permanent harm (pessimistically interpreted) occurred after two spinals, three CSEs, and one epidural. Without robust denominators, interpretation of these data is difficult, but we can be reassured that we did not uncover an epidemic of epiduralrelated harm after orthopaedic arthroplasty. T. M. Cook1* D. Counsell2 J. A. W. Wildsmith3 1 Bath, UK 2 Wrexham, UK 3 Dundee, UK *E-mail: [email protected] 1 Cook TM, Counsell D, Wildsmith JAW. Major complications of central neuraxial block: report on the Third National Audit Project of the Royal College of Anaesthetists. Br J Anaesth 2009; 102: 179 – 90 2 Buggy DJ. Editorial: central neuraxial block: defining the risk more clearly. Br J Anaesth 2009; 102: 151 – 3 3 http://www.rcoa.ac.uk/index.asp?PageID¼717 4 Moen V, Dahlgren N, Irestedt L. Severe neurological complications after central neuraxial block in Sweden 1990 – 1999. Anesthesiology 2004; 101: 950 –9 5 Cook TM, Mihai R, Wildsmith JAW. A national census of central neuraxial block in the UK: results of the snapshot phase of the Third National Audit Project of the Royal College of Anaesthetists. Anaesthesia 2008; 63: 143 – 6 6 Sage D, Fowler SJ. Major neurologic injury following regional anesthesia. In: Finucane BT ed. Complications of Regional Anesthesia, 2nd Edn. New York: Springer, 2007; 333– 53 doi:10.1093/bja/aep069
Clinical outcome benefits of pretreatment with levosimendan Editor—Recently, Tritapepe and colleagues1 reported that pretreatment with levosimendan in patients undergoing elective surgical myocardial revascularization results in
883
Downloaded from http://bja.oxfordjournals.org/ at UCSF Library on April 22, 2015
methodology we used to exclude cases of full recovery we may have missed cases that Moen would have included. Third, the distribution of complications differs markedly between the two studies. As an example, in Moen and colleagues’ paper almost 40% of complications were caused by meningitis or cauda equina syndrome: these same complications represent close to 7% of those reported to NAP3. Whether such differences are historical or geographical is likely to be impossible to determine but it suggests the population of injuries we studied was quite dissimilar. Finally, assuming Fowler’s figure is based on the 28 neurological complications that occurred after perioperative epidurals and CSEs: of these, five had almost complete or complete resolution of symptoms even at the time of notification so were, at worst, transient. Ten (including these five) made a documented full recovery within six months and, of the 28, only eight were included in the optimistic interpretation of the data. We therefore intentionally did not analyse our results on this basis and we discourage Fowler’s analysis of our data because we believe that it is not based on robust data capture or case analysis. Dr Fowler suggests that the project might (ideally) have been used to determine the risk of CNB for each surgical speciality (and by extrapolation perhaps for each operation). This would have required collection of data such as the indication for every CNB performed in the UK for a whole year. This is also true regarding resolving interesting questions such as whether CNB performed awake or anaesthetized is associated with more harm. We spent a considerable time deciding how much information to request from our colleagues in the census stage of the project, because it is only by determining denominator data that one can then calculate an incidence. We eventually decided that there was more to be gained by return of a limited amount of data from all hospitals, than extensive details from only a few. We believe we were vindicated in this decision by a 100% return rate in the census stage, but this figure should not hide the enormous amount of effort required to achieve such a return. We have no doubt at all that had we attempted to gain considerably more information at the census stage of the project, returns would have been low, and the project would have failed. Finally, Dr Fowler refers to work relating to lower limb arthroplasty and raises the possibility that total joint replacement and epidural anaesthesia are a particularly hazardous combination.6 Moen and colleagues’ data have also been reported in support of this contention.4 We discuss in some detail in our report why such subgroup analyses are potentially misleading, particularly when numerators and denominators are small, with the consequence of increasingly wide confidence intervals around any point estimate of risk. Regarding joint arthroplasty, in the period during which NAP3 ran, more than 100 000 lower limb arthroplasties were performed in the NHS in England and Wales ( personal communication
Correspondence
J. van den Brule C. Hoedemaekers P. Pickkers* Nijmegen, The Netherlands *E-mail: [email protected]
Editor—We thank Pickkers and colleagues for their insightful queries about our article. To address the first question raised, baseline EF was dichotomized as ,35% and .35%. The patients in the treatment group with an EF ,35% showed a significant reduction in ICU length of stay compared with the same subgroup of the controls [26.2 (4.8) vs 37.1 (11.9), Mann – Whitney U-test P¼0.0184]. As to the second point, Table 1 reports frequencies and percentage in treatment and control groups for ICU length of stay categorized in three classes. The overall association was assessed with Fisher’s exact test (P¼0.0051). In particular, the proportion of patients with ICU length of stay ,24 h was 48.1% in levosimendan and 28.0% in the control groups. To assess how time on ventilator and inotropes mediate levosimendan effect on ICU
Table 1 ICU length of stay. Data are frequencies (%). *P-value refers to Mann-Whitney U-test Variable
Class
Treatment
Control
P-value*
ICU stay
,24 h 24 –48 h 48 h
25 (48.1) 27 (51.9) 0 (0.0)
14 (28.0) 29 (58.0) 7 (14.0)
0.005
52
50
Total
length of stay, unadjusted and adjusted linear regression models for the log-transformed endpoint were used. Back-transformed marginal means for the unadjusted model were 23.9 in the levosimendan group and 30.3 in controls (P¼0.0007). After adjustment for time on ventilator (in tertiles) and received inotropes, marginal means did not change (24.4 vs 29.7, P¼0.0058). Similar results were obtained when a logistic model instead of a linear model was used, with a cutoff for ICU stay of ,24 or ,36 h. V. De Santis Rome, Italy E-mail: [email protected]
1 Tritapepe L, De Santis V, Vitale D, et al. Levosimendan pre-treatment improves outcomes in patients undergoing coronay artery bypass graft surgery. Br J Anaesth 2009; 102: 198 – 204 2 De Hert SG, Lorsomradee S, vanden Eede H, Cromheecke S, Van der Linden PJ. A randomized trial evaluating different modalities of levosimendan administration in cardiac surgery patients with myocardial dysfunction. J Cardiothorac Vasc Anesth 2008; 22: 699 – 705 3 Barisin S, Husedzinovic I, Sonicki Z, Bradic N, Barisin A, Tonkovic D. Levosimendan in off-pump coronary artery bypass: a four-times masked controlled study. J Cardiovasc Pharmacol 2004; 44: 703 – 8 doi:10.1093/bja/aep115
Cough during emergence from anaesthesia Editor—Hans and colleagues1 compare coughing after propofol- and sevoflurane-based anaesthesia in patients undergoing neck surgery. The results strongly support the use of propofol over sevoflurane in both smokers and nonsmokers. However, some important questions remain. First, the unequal distribution of remifentanil effect-site concentrations in the two groups at extubation favours the propofol group. In light of newer evidence that low-dose remifentanil does indeed reduce the incidence and severity of coughing after general anaesthesia,2 it could be argued that the final results of Hans and colleagues’ study were
884
Downloaded from http://bja.oxfordjournals.org/ at UCSF Library on April 22, 2015
less myocardial injury, a reduction in tracheal intubation time, less requirement for inotropic support, and a shorter ICU length of stay. This is the first study that demonstrates clinical outcome benefit with the use of levosimendan in such a patient population. Pretreatment with levosimendan has beneficial effects on myocardial function of patients with an impaired ejection fraction (EF)2 and also of patients with a normal EF.3 Following physiological principles, clinical outcome benefit is likely to be more relevant in patients with impaired cardiac function, but this has not been demonstrated in humans yet. In their study,1 95% of the studied patients had a baseline EF between 20% and 60%. This considerable variation would make it possible to correlate baseline EF with the beneficial effects of levosimendan. This additional analysis could possibly demonstrate that patients with an impaired EF treated with levosimendan need less inotropic support resulting in a shorter ICU stay. As these effects may not be of clinical relevance in patients with a better EF, a patient group more likely to benefit from levosimendan treatment can be identified. Secondly, the authors report that ICU length of stay was 12 h less on average in the levosimendan-treated group. As patients are not routinely discharged during evening or night hours, and to further emphasize the clinical relevance of this observation, it would be of interest to show the proportion of patients that had an ICU length of stay of 1, 2, or longer than 2 days. Moreover, in view of the differences between the levosimendan and the placebo groups in time on ventilator and number of patients on inotropes, in our opinion it would be of relevance to show how these endpoints interact with each other and mediate ICU length of stay.
Mr I. Mulcahy, National Joint Registry). As NAP3’s denominator also included Scotland and Northern Ireland, the denominator will considerably exceed 100 000 operations. Although the NJR data do not allow us to state, with confidence, how many of these operations were performed under CNB, nor how many under epidural, we can state that only one of the 50 adult perioperative nonobstetric cases reviewed by NAP3 (including those later excluded on the grounds of date of CNB or hospital funding) was a lower limb arthroplasty, in which epidural anaesthesia was the CNB. Of these 50 cases, 13 underwent orthopaedic surgery including eight primary joint replacements and two revision joint replacements. Six spinals and two combined spinal–epidurals (CSEs) were used for primary arthroplasty and one CSE and one epidural for the revision arthroplasties. Permanent harm (pessimistically interpreted) occurred after two spinals, three CSEs, and one epidural. Without robust denominators, interpretation of these data is difficult, but we can be reassured that we did not uncover an epidemic of epiduralrelated harm after orthopaedic arthroplasty. T. M. Cook1* D. Counsell2 J. A. W. Wildsmith3 1 Bath, UK 2 Wrexham, UK 3 Dundee, UK *E-mail: [email protected] 1 Cook TM, Counsell D, Wildsmith JAW. Major complications of central neuraxial block: report on the Third National Audit Project of the Royal College of Anaesthetists. Br J Anaesth 2009; 102: 179 – 90 2 Buggy DJ. Editorial: central neuraxial block: defining the risk more clearly. Br J Anaesth 2009; 102: 151 – 3 3 http://www.rcoa.ac.uk/index.asp?PageID¼717 4 Moen V, Dahlgren N, Irestedt L. Severe neurological complications after central neuraxial block in Sweden 1990 – 1999. Anesthesiology 2004; 101: 950 –9 5 Cook TM, Mihai R, Wildsmith JAW. A national census of central neuraxial block in the UK: results of the snapshot phase of the Third National Audit Project of the Royal College of Anaesthetists. Anaesthesia 2008; 63: 143 – 6 6 Sage D, Fowler SJ. Major neurologic injury following regional anesthesia. In: Finucane BT ed. Complications of Regional Anesthesia, 2nd Edn. New York: Springer, 2007; 333– 53 doi:10.1093/bja/aep069
Clinical outcome benefits of pretreatment with levosimendan Editor—Recently, Tritapepe and colleagues1 reported that pretreatment with levosimendan in patients undergoing elective surgical myocardial revascularization results in
883
Downloaded from http://bja.oxfordjournals.org/ at UCSF Library on April 22, 2015
methodology we used to exclude cases of full recovery we may have missed cases that Moen would have included. Third, the distribution of complications differs markedly between the two studies. As an example, in Moen and colleagues’ paper almost 40% of complications were caused by meningitis or cauda equina syndrome: these same complications represent close to 7% of those reported to NAP3. Whether such differences are historical or geographical is likely to be impossible to determine but it suggests the population of injuries we studied was quite dissimilar. Finally, assuming Fowler’s figure is based on the 28 neurological complications that occurred after perioperative epidurals and CSEs: of these, five had almost complete or complete resolution of symptoms even at the time of notification so were, at worst, transient. Ten (including these five) made a documented full recovery within six months and, of the 28, only eight were included in the optimistic interpretation of the data. We therefore intentionally did not analyse our results on this basis and we discourage Fowler’s analysis of our data because we believe that it is not based on robust data capture or case analysis. Dr Fowler suggests that the project might (ideally) have been used to determine the risk of CNB for each surgical speciality (and by extrapolation perhaps for each operation). This would have required collection of data such as the indication for every CNB performed in the UK for a whole year. This is also true regarding resolving interesting questions such as whether CNB performed awake or anaesthetized is associated with more harm. We spent a considerable time deciding how much information to request from our colleagues in the census stage of the project, because it is only by determining denominator data that one can then calculate an incidence. We eventually decided that there was more to be gained by return of a limited amount of data from all hospitals, than extensive details from only a few. We believe we were vindicated in this decision by a 100% return rate in the census stage, but this figure should not hide the enormous amount of effort required to achieve such a return. We have no doubt at all that had we attempted to gain considerably more information at the census stage of the project, returns would have been low, and the project would have failed. Finally, Dr Fowler refers to work relating to lower limb arthroplasty and raises the possibility that total joint replacement and epidural anaesthesia are a particularly hazardous combination.6 Moen and colleagues’ data have also been reported in support of this contention.4 We discuss in some detail in our report why such subgroup analyses are potentially misleading, particularly when numerators and denominators are small, with the consequence of increasingly wide confidence intervals around any point estimate of risk. Regarding joint arthroplasty, in the period during which NAP3 ran, more than 100 000 lower limb arthroplasties were performed in the NHS in England and Wales ( personal communication
Correspondence
J. van den Brule C. Hoedemaekers P. Pickkers* Nijmegen, The Netherlands *E-mail: [email protected]
Editor—We thank Pickkers and colleagues for their insightful queries about our article. To address the first question raised, baseline EF was dichotomized as ,35% and .35%. The patients in the treatment group with an EF ,35% showed a significant reduction in ICU length of stay compared with the same subgroup of the controls [26.2 (4.8) vs 37.1 (11.9), Mann – Whitney U-test P¼0.0184]. As to the second point, Table 1 reports frequencies and percentage in treatment and control groups for ICU length of stay categorized in three classes. The overall association was assessed with Fisher’s exact test (P¼0.0051). In particular, the proportion of patients with ICU length of stay ,24 h was 48.1% in levosimendan and 28.0% in the control groups. To assess how time on ventilator and inotropes mediate levosimendan effect on ICU
Table 1 ICU length of stay. Data are frequencies (%). *P-value refers to Mann-Whitney U-test Variable
Class
Treatment
Control
P-value*
ICU stay
,24 h 24 –48 h 48 h
25 (48.1) 27 (51.9) 0 (0.0)
14 (28.0) 29 (58.0) 7 (14.0)
0.005
52
50
Total
length of stay, unadjusted and adjusted linear regression models for the log-transformed endpoint were used. Back-transformed marginal means for the unadjusted model were 23.9 in the levosimendan group and 30.3 in controls (P¼0.0007). After adjustment for time on ventilator (in tertiles) and received inotropes, marginal means did not change (24.4 vs 29.7, P¼0.0058). Similar results were obtained when a logistic model instead of a linear model was used, with a cutoff for ICU stay of ,24 or ,36 h. V. De Santis Rome, Italy E-mail: [email protected]
1 Tritapepe L, De Santis V, Vitale D, et al. Levosimendan pre-treatment improves outcomes in patients undergoing coronay artery bypass graft surgery. Br J Anaesth 2009; 102: 198 – 204 2 De Hert SG, Lorsomradee S, vanden Eede H, Cromheecke S, Van der Linden PJ. A randomized trial evaluating different modalities of levosimendan administration in cardiac surgery patients with myocardial dysfunction. J Cardiothorac Vasc Anesth 2008; 22: 699 – 705 3 Barisin S, Husedzinovic I, Sonicki Z, Bradic N, Barisin A, Tonkovic D. Levosimendan in off-pump coronary artery bypass: a four-times masked controlled study. J Cardiovasc Pharmacol 2004; 44: 703 – 8 doi:10.1093/bja/aep115
Cough during emergence from anaesthesia Editor—Hans and colleagues1 compare coughing after propofol- and sevoflurane-based anaesthesia in patients undergoing neck surgery. The results strongly support the use of propofol over sevoflurane in both smokers and nonsmokers. However, some important questions remain. First, the unequal distribution of remifentanil effect-site concentrations in the two groups at extubation favours the propofol group. In light of newer evidence that low-dose remifentanil does indeed reduce the incidence and severity of coughing after general anaesthesia,2 it could be argued that the final results of Hans and colleagues’ study were
884
Downloaded from http://bja.oxfordjournals.org/ at UCSF Library on April 22, 2015
less myocardial injury, a reduction in tracheal intubation time, less requirement for inotropic support, and a shorter ICU length of stay. This is the first study that demonstrates clinical outcome benefit with the use of levosimendan in such a patient population. Pretreatment with levosimendan has beneficial effects on myocardial function of patients with an impaired ejection fraction (EF)2 and also of patients with a normal EF.3 Following physiological principles, clinical outcome benefit is likely to be more relevant in patients with impaired cardiac function, but this has not been demonstrated in humans yet. In their study,1 95% of the studied patients had a baseline EF between 20% and 60%. This considerable variation would make it possible to correlate baseline EF with the beneficial effects of levosimendan. This additional analysis could possibly demonstrate that patients with an impaired EF treated with levosimendan need less inotropic support resulting in a shorter ICU stay. As these effects may not be of clinical relevance in patients with a better EF, a patient group more likely to benefit from levosimendan treatment can be identified. Secondly, the authors report that ICU length of stay was 12 h less on average in the levosimendan-treated group. As patients are not routinely discharged during evening or night hours, and to further emphasize the clinical relevance of this observation, it would be of interest to show the proportion of patients that had an ICU length of stay of 1, 2, or longer than 2 days. Moreover, in view of the differences between the levosimendan and the placebo groups in time on ventilator and number of patients on inotropes, in our opinion it would be of relevance to show how these endpoints interact with each other and mediate ICU length of stay.