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Published in: Trials 1/2016

Open Access 01-12-2016 | Study protocol

Perfusion Pressure Cerebral Infarct (PPCI) trial - the importance of mean arterial pressure during cardiopulmonary bypass to prevent cerebral complications after cardiac surgery: study protocol for a randomised controlled trial

Authors: Anne G. Vedel, Frederik Holmgaard, Lars Simon Rasmussen, Olaf B. Paulson, Carsten Thomsen, Else Rubæk Danielsen, Annika Langkilde, Jens P. Goetze, Theis Lange, Hanne Berg Ravn, Jens C. Nilsson

Published in: Trials | Issue 1/2016

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Abstract

Background

Debilitating brain injury occurs in 1.6–5 % of patients undergoing cardiac surgery with cardiopulmonary bypass. Diffusion-weighted magnetic resonance imaging studies have reported stroke-like lesions in up to 51 % of patients after cardiac surgery. The majority of the lesions seem to be caused by emboli, but inadequate blood flow caused by other mechanisms may increase ischaemia in the penumbra or cause watershed infarcts. During cardiopulmonary bypass, blood pressure can be below the lower limit of cerebral autoregulation. Although much debated, the constant blood flow provided by the cardiopulmonary bypass system is still considered by many as appropriate to avoid cerebral ischaemia despite the low blood pressure.

Methods/design

The Perfusion Pressure Cerebral Infarct trial is a single-centre superiority trial with a blinded outcome assessment. The trial is randomising 210 patients with coronary vessel and/or valve disease and who are undergoing cardiac surgery with the use of cardiopulmonary bypass. Patients are stratified by age and surgical procedure and are randomised 1:1 to either an increased mean arterial pressure (70–80 mmHg) or ‘usual practice’ (40–50 mmHg) during cardiopulmonary bypass.
The cardiopulmonary bypass pump flow is fixed and set at 2.4 L/minute/m2 body surface area plus 10–20 % in both groups.
The primary outcome measure is the volume of the new ischaemic cerebral lesions (in mL), expressed as the difference between a baseline, diffusion-weighted, magnetic resonance imaging scan and an equal scan conducted 3–6 days postoperatively. Secondary endpoints are the total number of new ischaemic cerebral lesions, postoperative cognitive dysfunction at discharge and 3 months postoperatively, diffuse cerebral injury evaluated by magnetic resonance spectroscopy and selected biochemical markers of cerebral injury.
The sample size will enable us to detect a 50 % reduction in the primary outcome measure in the intervention compared to the control group at a significance level of 0.05 and with a power of 0.80.

Discussion

This is the first clinical randomised study to evaluate whether the mean arterial pressure level during cardiopulmonary bypass influences the development of brain injuries that are detected by diffusion-weighted magnetic resonance imaging.

Trial registration

ClinicalTrials.gov, NCT02185885. Registered on 7 July 2014.
Appendix
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Literature
1.
Roach GW Kanchuger M, Mangano CM, Newman M, Nussmeier N, Wolman R, et al. Adverse cerebral outcomes after coronary bypass surgery. Multicenter study of Perioperative Ischemia Research Group and the Ischemia Research and Education Foundation Investigators. N Engl J Med. 1996;335:1857–63.CrossRefPubMed
2.
Salazar JD Wityk RJ, Grega M a, Borowicz LM, Doty JR, Petrofski Ja et al. Stroke after cardiac surgery: short- and long-term outcomes. Ann Thorac Surg. 2001;72:1195–201.CrossRefPubMed
3.
Tarakji KG, Sabik JF, Batizy LH, Blackstone EH, Is T, Com AD. Temporal onset, risk factors and outcomes associated with stroke after coronary artery bypass grafting. JAMA. 2011;305:381–90.CrossRefPubMed
4.
Ahonen J, Salmenperä M. Brain injury after adult cardiac surgery. Acta Anaesthesiol Scand. 2004;48:4–19.CrossRefPubMed
5.
Bendszus M, Reents W, Franke D, Mullges W, Babin-Ebell J, Koltzenburg M, et al. Brain damage after coronary artery bypass grafting. Arch Neurol. 2002;59:1090-5.
6.
Knipp SC, Matatko N, Wilhelm H, Schlamann M, Thielmann M, Lösch C et al. Cognitive outcomes three years after coronary artery bypass surgery: relation to diffusion-weighted magnetic resonance imaging. Ann Thorac Surg. 2008;85:872–9.CrossRefPubMed
7.
Barber PA, Hach S, Tippett LJ, Ross L, Merry AF, Milsom P. Cerebral ischemic lesions on diffusion-weighted imaging are associated with neurocognitive decline after cardiac surgery. Stroke. 2008;39:1427–33.CrossRefPubMed
8.
Knipp SC, Matatko N, Schlamann M, Wilhelm H, Thielmann M, Forsting M, et al. Small ischemic brain lesions after cardiac valve replacement detected by diffusion-weighted magnetic resonance imaging: relation to neurocognitive function. Eur J Cardio-thoracic Surg. 2005;28:88–96.CrossRef
9.
Lassen NA. Cerebral blood flow and oxygen consumption in man. Physiol Rev. 1959;39:183–238.PubMed
10.
McCALL ML. Cerebral circulation and metabolism in toxemia of pregnancy: observations on the effects of veratrum viride and apresoline (1-hydrazinophthalazine). Am J Obstet Gynecol. 1953;66:1015–30.PubMed
11.
12.
Schell RM, Kern FH, Greeley WJ, Schulman SR, Frasco PE, Croughwell ND, et al. Cerebral blood flow and metabolism during cardiopulmonary bypass. Anesth Analg. 1993;76:849–65.CrossRefPubMed
13.
O’Dwyer C, Woodson LC, Conroy BP, Lin CY, Deyo DJ, Uchida T, et al. Regional perfusion abnormalities with phenylephrine during normothermic bypass. Ann Thorac Surg. 1997;63:728–35.CrossRefPubMed
14.
15.
Philpott JM, Eskew TD, Sun YS, Dennis KJ, Foreman BH, Fairbrother SN, et al. A paradox of cerebral hyperperfusion in the face of cerebral hypotension: the effect of perfusion pressure on cerebral blood flow and metabolism during normothermic cardiopulmonary bypass. J Surg Res. 1998;77:141–9.CrossRefPubMed
16.
Govier AV, Reves JG, McKay RD, Karp RB, Zorn GL, Morawetz RB, et al. Factors and their influence on regional cerebral blood flow during nonpulsatile cardiopulmonary bypass. Ann Thorac Surg. 1984;38:592–600.CrossRefPubMed
17.
Murkin JM, Farrar JK, Tweed WA, McKenzie FN, Guiraudon G. Cerebral autoregulation and flow/metabolism coupling during cardiopulmonary bypass: the influence of PaCO2. Anesth Analg. 1987;66:825–32.CrossRefPubMed
18.
Slogoff S, Reul GJ, Keats AS, Curry GR, Crum ME, Elmquist BA, et al. Role of perfusion pressure and flow in major organ dysfunction after cardiopulmonary bypass. Ann Thorac Surg. 1990;50:911–8.CrossRefPubMed
19.
van Wermeskerken GK, Lardenoye JW, Hill SE, Grocott HP, Phillips-Bute B, Smith PK, et al. Intraoperative physiologic variables and outcome in cardiac surgery: part ii. neurologic outcome. Ann Thorac Surg. 2000;69:1077–83.CrossRefPubMed
20.
Drummond JC. The lower limit of autoregulation: time to revise our thinking? Anesthesiology. 1997;86:1431–3.CrossRefPubMed
21.
Brady K, Joshi B, Zweifel C, Smielewski P, Czosnyka M, Easley RB, et al. Real-time continuous monitoring of cerebral blood flow autoregulation using near-infrared spectroscopy in patients undergoing cardiopulmonary bypass. Stroke. 2010;41:1951–6.CrossRefPubMed
22.
Charlson ME, Peterson JC, Krieger KH, Hartman GS, Hollenberg JP, Briggs WM, et al. Improvement of outcomes after coronary artery bypass II: a randomized trial comparing intraoperative high versus customized mean arterial pressure. J Card Surg. 2007;22:465–72.CrossRefPubMed
23.
Strandgaard S, Paulson OB. Regulation of cerebral blood flow in health and disease. J Cardiovasc Pharmacol. 1992;19 Suppl 6:S89–93.CrossRefPubMed
24.
Liu Y, Wang H, Liu Y, Yang X, Gong H, Jiang B, et al.. Assessing the effects of norepinephrine on single cerebral microvessels using optical-resolution photoacoustic microscope cerebral microvessels using optical-resolution. doi:10.​1117/​1.​JBO.​18.​7
25.
Wahl M, Kuschinsky W, Bosse O, Olesen J, Lassen N a, Ingvar DH, et al. Effect of 1-norepinephrine on the diameter of pial arterioles and arteries in the cat. Circ Res. 1972;31:248–56.CrossRefPubMed
26.
MacKenzie ET, McCulloch J, O’Kean M, Pickard JD, Harper AM. Cerebral circulation and norepinephrine: relevance of the blood–brain barrier. Am J Physiol. 1976;231:483–8.PubMed
27.
Dünser MW, Hasibeder WR. Sympathetic overstimulation during critical illness: adverse effects of adrenergic stress. J Intensive Care Med. 2015;24:293–316.CrossRef
28.
Gold JP, Reves JG, White WD, Amory DW. Improvement of outcomes after coronary artery bypass. A randomized trial comparing intraoperative high versus low mean arterial pressure. J Thorac Cardiovasc Surg. 1995;110:1302–11. discussion 1311–4.CrossRefPubMed
29.
Siepe M, Pfeiffer T, Gieringer A, Zemann S, Benk C, Schlensak C, et al. Increased systemic perfusion pressure during cardiopulmonary bypass is associated with less early postoperative cognitive dysfunction and delirium. Eur J Cardiothorac Surg. 2011;40:200–7.CrossRefPubMed
30.
Murphy GS, Hessel EA, Groom RC. Optimal perfusion during cardiopulmonary bypass: an evidence-based approach. Anesth Analg. 2009;108:1394–417.CrossRefPubMed
31.
32.
Seco M, Edelman JJB, Wilson MK, Bannon PG, Vallely MP. Serum biomarkers of neurologic injury in cardiac operations. Ann Thorac Surg. 2012;94:1026–33.CrossRefPubMed
33.
Cata JP, Abdelmalak B, Farag E. Neurological biomarkers in the perioperative period. Br J Anaesth. 2011;107:844–58.CrossRefPubMed
34.
Moller JT, Cluitmans P, Rasmussen LS, Houx P, Rasmussen H, Canet J, et al. Long-term postoperative cognitive dysfunction in the elderly ISPOCD1 study. ISPOCD investigators. International Study of Post-Operative Cognitive Dysfunction. Lancet (London, England). 1998;351:857–61.CrossRef
35.
De Backer D, Hollenberg S, Boerma C, Goedhart P, Büchele G, Ospina-Tascon G, et al. How to evaluate the microcirculation: report of a round table conference. Crit Care. 2007;11:R101.
36.
Dodonov M, Milano A, Onorati F, Dal Corso B, Menon T, Ferrarini D, et al. Gaseous micro-emboli activity during cardiopulmonary bypass in adults: pulsatile flow versus nonpulsatile flow. Artif Organs. 2013;37:357–67.
37.
Lou S, Ji B, Liu J, Yu K, Long C. Generation, detection and prevention of gaseous microemboli during cardiopulmonary bypass procedure. Int J Artif Organs. 2011;34:1039–51.CrossRefPubMed
38.
Bevan PJW. Should cerebral near-infrared spectroscopy be standard of care in adult cardiac surgery? Heart Lung Circ. 2015;24:544–50.CrossRefPubMed
39.
Slater JP, Guarino T, Stack J, Vinod K, Bustami RT, Brown JM, et al. Cerebral oxygen desaturation predicts cognitive decline and longer hospital stay after cardiac surgery. Ann Thorac Surg. 2009;87:36–44. discussion 44–5.CrossRefPubMed
40.
Meller SM, Baumbach A, Brickman AM, Lansky AJ. Clinical implications for diffusion-weighted MRI brain lesions associated with transcatheter aortic valve replacement. Catheter Cardiovasc Interv. 2014;83:502–8.CrossRefPubMed
41.
Deneke T, Jais P, Scaglione M, Schmitt R, DI Biase L, Christopoulos G, et al. Silent cerebral events/lesions related to atrial fibrillation ablation: a clinical review. J Cardiovasc Electrophysiol. 2015;26:455–63.CrossRefPubMed
42.
Danielsen ER, Lund AM, Thomsen C. Cerebral magnetic resonance spectroscopy demonstrates long-term effect of bone marrow transplantation in α-mannosidosis. JIMD Rep. 2013;11:49–52.CrossRefPubMedPubMedCentral
43.
Kahan BC, Morris TP. Reporting and analysis of trials using stratified randomisation in leading medical journals: review and reanalysis. BMJ. 2012;345:e5840.CrossRefPubMedPubMedCentral
44.
Kahan BC, Morris TP. Improper analysis of trials randomised using stratified blocks or minimisation. Stat Med. 2012;31:328–40.CrossRefPubMed
45.
Fergusson D, Aaron SD, Guyatt G, Hébert P. Post-randomisation exclusions: the intention to treat principle and excluding patients from analysis. BMJ. 2002;325:652–4.CrossRefPubMedPubMedCentral
Metadata
Title
Perfusion Pressure Cerebral Infarct (PPCI) trial - the importance of mean arterial pressure during cardiopulmonary bypass to prevent cerebral complications after cardiac surgery: study protocol for a randomised controlled trial
Authors
Anne G. Vedel
Frederik Holmgaard
Lars Simon Rasmussen
Olaf B. Paulson
Carsten Thomsen
Else Rubæk Danielsen
Annika Langkilde
Jens P. Goetze
Theis Lange
Hanne Berg Ravn
Jens C. Nilsson
Publication date
01-12-2016
Publisher
BioMed Central
Published in
Trials / Issue 1/2016
Electronic ISSN: 1745-6215
DOI
https://doi.org/10.1186/s13063-016-1373-6

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