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Reply to Drs Guha, Lakhani and Whitehead
- peter kimme, Magnus Vegfors, Folke Sjöberg, Jan Hillman (22 March 2005)
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Moderate hypothermia for 359 operations to clip cerebral aneurysms
- Arpan Guha, Dr Lakhani, Dr Whitehead (22 March 2005)
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peter kimme, Anaesthetist University Hospital, Linkoping, Sweden, Magnus Vegfors, Folke Sjöberg, Jan Hillman
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Editor, We appreciate the interest of Drs Guha, Lakhani and Whitehead in our study1. We thank them for their thorough reading of our article and we will try to resolve some of their concerns. First, we would like to highlight the rationale for the protocol, which is described in the article and its relation to present knowledge. In order to understand why it was constructed as presented the evolution and practise of neuroanesthesia during the last ten years needs to be recalled. When the protocol was first planned (1993)much interest and hope was at the time linked to hypothermia for brain tissue ischemia protection based mainly on experimental studies and case-reports which lead to the wide spread of its use - approximately 60% of the UK centres has said to use hypothermia in connection with SAH-surgery2 . Since then, there have been extensive research performed with somewhat contradicting results. Two articles concerning global ischemia after cardiac arrest have lead to a wide recognition of its benefit as a global brain saving therapy 3-4. However, Clifton and co-workers5 were unable to find any support for its use in the treatment of traumatic brain injury. Furthermore, the recently well conducted, prospective and randomized controlled trial by Todd and co-workers6 failed to show any support for hypothermia when applied to patients that are operated on for subarachnoidal haemorrhage. This study included also the important subgroup, which was subjected to the use of temporal clips. These studies, as well as is the case with the references cited by Drs. Guha, Lakhani and Whitehead, were mostly published after the completion of our study (Dec 1999) and of course where not available for us when we planned and performed our study. However, these studies, including our own, as well as the ongoing debate helps create new knowledge and further improvement of our therapies. Still, confronted with the emerging knowledge on a possible lack of treatment effect of hypothermia in the end of the nineties especially for the subarachnoidal patient group we thought it important to present our results as they provide insight into the possible side effects/safety of a short perioperative hypothermia protocol. Not least as it has been a common practice in a significant number of neuroanesthesia centers in the United Kindom2 . It is important also to underline the fact that we found comparatively few complications that could specifically be connected to our protocol and how it was used7. Our procedure and findings may be of value also for other future studies of hypothermia and brain protection e.g., in the field of cardiac arrest and/or stroke8. We also think it is important to note that in the period in which we did our study a general treatment paradigm change has occurred with a presently large demand in having all or most treatments founded in evidence based strategies. In the early 90-ties significantly less focus was directed to having all treatment strategies fully evidence based. Secondly, we would like to address the specific questions posed by Drs. Guha, Lakhani and Whitehead. In doing so we have chosen what we gather the four main topics raised in their letter. 1. Removal of blood. This was performed primarily in order to facilitate the intravenous induction of hypothermia. It was also, to some extent aimed at improving the microvascular rheological properties. Decreasing the hematocrit and adding crystalloid has been claimed to decrease the viscosity of the blood and thereby improving the microvascular rheology. However, such evidence exist mainly for the use of rheomacrodex9 and the scientific foundation for such a procedure as done in our protocol is not very strong. The transfusion strategy was also aimed at increasing the intravascular volume, i.e., as a part of the conventional triple H (Hypertension, hypervolemia and haemodilution) therapy10 . We would at this point like to acknowledge the mistake made in our text, the correct figure should be the one mentioned in table 2. However, we would like to underline that this is a study dealing with the safety of a hypothermic protocol and the reported number of patients who received blood transfusions during the perioperative period does not imply that they were either hemodynamically unstable or prone to bleed. In fact as is stated in the same Table, only 4 patients were specifically identified having haemostasis problems and since in this heterogeneous material (Hunt & Hess I-V) there were several patients with ongoing medications known to affect haemostasis. Furthermore, the choice of a transfusion level of 2 or 3 units of blood is only an arbitrary measure and was chosen as a baseline. This transfusion practice was based on several, albeit scientifically not very strong arguments apart from the Tripe H therapy. One major reason for the large number of patients, n=101 (28%), who received 1-2 units of blood where to reach the target Haemoglobin of 12g/dl, which is a slightly higher level than what we today claim from an evidence based viewpoint. Furthermore, we would like to highlight the shortcomings in the reasoning by Drs. Guha, Lakhani and Whitehead in that they claim that blood transfusions in themselves worsens outcome in SAH surgery. This reasoning is flawed as the more difficult cases, i.e., those with ruptured aneurysms, needing transfusion are by the nature of their illness at risk for a worse prognosis. This may then be a parallel phenomenon rather than the causative action. 2. Inotropic support. Again we agree with Drs Guha, Lakhani and Whitehead that the incidence of patients that required inotropic support was high, however it is our judgement that this was not primarily associated with the induction of the protocol, i.e., withdrawal of blood since only 10% (n=36) received treatment for circulatory instability. One hundred and thirteen of the operated patients were intubated outside the OR (referring hospital/NICU/ER) and the majority of these patients had a (low-) dose inotropic treatment to keep adequate CPP (cerebral perfusion pressure (target 70-75 mmHg)) and the patient group also received low-dose dopamine in a ¡§kidney protective dose¡¨ (and we are well aware of the present lack of evidence for this indication as well11 . At the time however, this treatment modality was claimed efficient12 We would like to stress that the inotropic support was also provided as a part of the triple H therapy. It needs to be stressed that the patient group after being intubated and sedated prior to surgery loose some of their sympathetic tone, leading to a decrease in pressure. This may also lead to an indication for inotropes. 3. Barbiturate. The dose 15mg/kg/BW was empirically chosen. Its use was mainly to ease and to increase the speed of onset of hypothermia in conjunction to reducing both intracranial pressure as well as the oxygen consumption of the brain and thereby to potentially reduce any ischemia induced brain injuries. Today, however there are studies indicating that such an effect is lacking, albeit these studies are mainly done in traumatic brain injured patients13. The dose was chosen large enough to lead to corresponding burst suppression in almost all patients. 4. Not randomised study. We did not randomize the study as we (as so many other centers) relied on the at the times existing experimental data and case-reports, which suggested positive brain protection effect. Furthermore, in our own pilot results (not published) we did not find any significant complications related to the hypothermic protocol. This finding is also strengthened by our presented results of the whole material. At the time when looking at power calculations we also realized early that the numbers that we could gather within a reasonable time (we gathered 325 patients during 6 years) would not even be close to the numbers needed for a conclusion on the topic such as recently done by Todd and co-workers6 (they gathered 1000 patients hypothermia = 499 and control = 501). However the protocol would be valid to be able to conclude on the safety of a short period of perioperative hypothermia1. Concluding remarks; In recognition of the results from Todd and co- workers6 and also from influence of the ongoing debate (as for instance these letters) we have recently changed our protocol and do not routinely induce hypothermia and have also excluded barbiturate (except for induction of anaesthesia in a standard dose) in connection with SAH- surgery. The value of the present study lies in that it shows that hypothermia in man can be induced rapidly perioperatively and reversed in a short period of time without major complications. 1. Kimme P, Fridrikssen S, Engdahl O,et al. Moderate hypothermia for 359 operations to clip cerebral aneurysms. British Journal of Anesthesia 2004:93:343-347 2. Pemberton PL, Dinsmore J. The use of hypothermia as a method of neuroprotection during neurosurgical procedures and after traumatic brain injury: a survey of clinical practice in Great Britain and Ireland. Anesthesia 2003:58:370-373 3. The hypothermia after cardiac arrest study group. Mild therapeutic hypothermia to improve the neurological outcome after cardiac arrest. N Engl J Med 2002:346:549-556 4. Bernard SA, Gray TW, Buist MD, et al. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med 2002:346:557-563 5. Clifton GL, Miller ER, Choi SC, et al. Lack of effect of induction of hypothermia after acute brain injury. N Engl J Med 2001:344:556-563 6. Todd MM, Hindman BJ, Clarke WR, et al, for the intraoperative hypothermia for aneurysm surgery trial (IHAST) investigators: Mild introperative hypothermia during surgery for intracranial aneurysm. N Engl J Med 2005:352:135-145 7. Solenski NJ, Haley EC Jr, Kassell NF, et al. Medical complications of aneurysmal subarachnoid hemorrhage: a report of the multicenter, cooperative aneurysm study. Participants of the Multicenter Cooperative Aneurysm Study. Critical Care Medicine 1995:23:1007-1017 8. Todd MM. Current status of hypothermia as a treatment modality. Can J Anesth 2004:51:R1-R3 9. Mazzoni MC, Borgstrom P, Intaglietta M, et al. Capillary narrowing in hemorrhagic shock is rectified by hyperosmotic saline-dextran reinfusion Circulatory Shock 1990:31:407-418 10. Awad IA, Carter LP, Spetzler RF, et al. Clinical vasospasm after subarachnoid hemorrhage: response to hypervolemic hemodilution and arterial hypertension. Stroke 1987:18:365-372 11. Holmes CL, Walley KR. Bad medicine: low-dose dopamine in the ICU. Chest 2003:123:1266-1275 12. Hans B, Hans SS, Mittal VK, et al. Renal functional response to dopamine during and after arteriography in patients with chronic renal insufficiency. Radiology 1990:176:651-654 13. Roberts I. Barbiturates for acute traumatic brain injury. The Cochrane Database of Systematic Reviews 1999, Issue 3, Art. No.: CD000033.DOI:10.1002/ 14651858.CD000033 |
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Arpan Guha, Consultant Anaesthetist university Hsopital Aintree and Walton Centre, Liverpool, Dr Lakhani, Dr Whitehead
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We read with interest the paper published recently in the September 2004 issue of your journal. As neuroanaesthetists working in a large neurosciences hospital in the UK, we would like to make a few comments. The protocol followed in their study allowed removal of 450 ml of blood from the patient after induction. Patients were then administered 2000 - 3000 ml of 0.9 % saline and 500 ml of hetastarch. The rationale behind this is unclear. We presume that this was carried out to facilitate hypervolaemia and haemodilution and facilitate blood flow in the cerebral microcirculation. We find this perioperative management disturbing. Lennihan’s randomised controlled work1 failed to find any difference in treatment benefit in normovolaemic and hypervolaemic patients with SAH. There was no difference in mean global cerebral blood flow, as measured using xenon clearance in Lennihan’s study, during the treatment period between the groups, and the incidence of symptomatic vasospasm was equal in both groups ( 20% ). We further question the wisdom of withdrawing the same blood volume in all patients without linking that to their total blood volume and body weight. It is well recognised that pulmonary oedema occurs in 17% of patients with SAH, especially after very high crystalloid volume expansion 2. It was also not clear why the authors then transfused blood, if required, post-operatively to achieve a haemoglobin concentration of 12 g dl–1 . Indeed, 44 % ( table 2 of their paper ) of patients received intraoperative blood transfusion after initial removal of blood ! However, in the discussion, the authors mention that “Although there were 266 ruptured aneurysms, only 74 ( 27% ) of our patients were given blood transfusions perioperatively”. A recent study3 has shown that angiographically confirmed cerebral vasospasm after SAH is associated with postoperative blood transfusion. A worse outcome was also reported in the same paper with intraoperative blood transfusion. Hence intraprocedure or post – procedure blood transfusion should be avoided in patients with SAH unless strongly indicated. The incidence of patients requiring inotropic support was high at 61 % ( Table 2 of the article ), and is far in excess of what we would normally see in our hospital. We feel that this may have resulted from the initial and unnecessary blood volume manipulations that were carried out against the backdrop of induced hypothermia. We would also wish to seek clarification on the use of 15 mg/kg of thiopental at induction. Once again, we presume that this was to aid cerebral protection. Cerebral protection with barbiturate induced coma has many adverse effects, including cardiorespiratory depression, increased risk of infection and electrolyte abnormalities. Indeed the use of thiopental in these situations was examined and found to have a detrimental effect two decades ago4. We acknowledge that a case series of 11 patients5 described 10 patients with an improved outcome with resolution of vasospasm with thiopental treatment. However, thiopental was used appropriately in that series with monitoring of burst suppression electroencephalogram ( EEG ), although comparisons were made against historical controls. It is, therefore, our concern that a high dose of thiopental was used with no brain monitoring and quite empirically. The authors state in their introduction that they pursue an “ aggressive anti –ischaemic adjunctive treatment based on several principles, of which perioperative moderate ( 32 – 34°C ) hypothermia is the most important ”. There is no conclusive human data to support the use of hypothermia as being neuro – protective in the clinical setting of sub - arachnoid haemorrhage ( SAH ). Indeed, the beneficial effect in cardiac arrest patients6 is against a background of global neural flow deficit and cannot be compared with the localised perfusion problems in SAH. The present trial was not randomised, and hence, all patients were subjected to hypothermic treatment by the authors, which is based on poor evidence. To then carry out a study to look for complications of such treatment is itself extremely flawed. The authors’ reasoning that this was justified because the study was carried out at a single centre and that patient numbers were limited is astonishing. Finally, the Intraoperative Hypothermia for Aneurysm Surgery Trial, Part 2 ( IHAST 2 ), which was set up to investigate the neuroprotective efficacy of mild intraoperative hypothermia ( target core temperature 33°C ) during open craniotomies performed to clip intracranial aneurysms has shown that there were no significant differences in the duration of intensive care unit stay or total length of hospitalization compared to normothermic management. At final follow - up, 65.9% of hypothermic patients ( n=499 ) had a Glasgow Outcome Score of 1 ( good outcome ) vs. 62.7% of normothermic patients ( n=501 )7 It is, therefore, clear that not only is intraoperative hypothermia not beneficial for patients undergoing repair of intracranial aneurysms, following the basic tenets of neuroanaesthesia is of greater importance than the use of questionable anaesthetic techniques. References : 1. Lennihan, L, Mayer SA Fink, M E Beckford, A, Paik MC, Zhang H, Wu YC, Klebanoff LM, Raps EC, Solomon RA. Effect of hypervolemic therapy on cerebral blood flow after subarachnoid hemorrhage : a randomized controlled trial. Stroke. 2000; 31(2),383-391 2. Sen J, Belli A, Albon H, Morgan L, Petzold A, Kitchen N. Triple-H therapy in the management of aneurysmal subarachnoid haemorrhage. The Lancet Neurology. 2003; 29(10), 614-620 3. Smith MJ,. Le Roux PD, Elliot JP,Winn HR. Blood transfusion and increased risk for vasospasm and poor outcome after subarachnoid hemorrhage. J Neurosurg. 2004;101(1):1-7. 4. Kassell NF, Peerless SJ, Drake CG, Boarini DJ, Adams HP.Treatment of ischemic deficits from cerebral vasospasm with high dose barbiturate therapy. Neurosurgery. 1980; 7(6):593-7 5. Finfer, S R; Ferch, R; Morgan, M K. Barbiturate coma for severe, refractory vasospasm following subarachnoid haemorrhage. Int Care Med.1999; 25(4), 406-409 6. Hypothermia after Cardiac Arrest Study Group. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med. 2002 ;346(8):549-56 7. http://www.ns2004.jp/program3/syoroku/MS-2-1.htm Conflict of Interest:None declared |
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