Full Text View
Study protocol and statistical analysis plan for the 20% Human Albumin Solution Fluid Bolus Administration Therapy in Patients after Cardiac Surgery-II (HAS FLAIR-II) trial
Geoffrey Wigmore*†, Rinaldo Bellomo*†, Adam M Deane, James Anstey, Michael Bailey, Shailesh Bihari, Glenn Eastwood, Rashmi Ghanpur, Matthew J Maiden, Jeffrey J Presneill, Jaishankar Raman, The HAS FLAIR-II trial investigators
Crit Care Resusc 2022; 24 (4): 309-18
- Geoffrey Wigmore*† 1, 2
- Rinaldo Bellomo*† 2, 3
- Adam M Deane 2, 4
- James Anstey 2, 4
- Michael Bailey 5
- Shailesh Bihari 6
- Glenn Eastwood 3
- Rashmi Ghanpur 3, 7
- Matthew J Maiden 8, 9, 10
- Jeffrey J Presneill 2, 4, 5
- Jaishankar Raman 11, 12, 13, 14
- The HAS FLAIR-II trial investigators
* Equal first authors.
† Corresponding author.
All authors declare that they do not have any potential conflict of interest in relation to this manuscript.
BACKGROUND: Fluid bolus therapy with 20% albumin may shorten the duration of vasopressor therapy in patients after cardiac surgery.
OBJECTIVE: To describe the study protocol and statistical analysis plan for the 20% Human Albumin Solution Fluid Bolus Administration Therapy in Patients after Cardiac Surgery-II (HAS FLAIR-II) trial.
DESIGN, SETTING, PARTICIPANTS AND INTERVENTION: HAS FLAIR-II is a phase 2b, multicentre, parallel group, open-label, randomised controlled trial that will be conducted at six Australian intensive care units. Patients requiring fluid bolus therapy after cardiac surgery will be randomly assigned in a 1:1 ratio to the intervention of fluid bolus therapy with 20% albumin or a comparator of fluid bolus therapy with a crystalloid solution.
MAIN OUTCOME MEASURES: The primary outcome measure is the cumulative duration of vasopressor therapy. Secondary outcomes include vasopressor use, service utilisation, and mortality. All analyses will be conducted on an intention-to-treat basis.
RESULTS AND CONCLUSION: The study protocol and statistical analysis plan will guide the conduct and analysis of the HAS FLAIR-II trial, such that analytical and reporting biases are minimised.
TRIAL REGISTRATION: This trial has been registered with the Australian New Zealand Clinical Trials Registry (ACTRN No. 12620000137998).
- Cengic S, Zuberi M, Bansal V, et al. Hypotension after intensive care unit drop-off in adult cardiac surgery patients. World J Crit Care Med 2020; 9: 20-30
- Parke RL, McGuinness SP, Gilder E, et al. Intravenous fluid use after cardiac surgery: a multicentre, prospective, observational study. Crit Care Resusc 2014; 16: 164
- Sedrakyan A, Gondek K, Paltiel D, et al. Volume expansion with albumin decreases mortality after coronary artery bypass graft surgery. Chest 2003; 123: 1853-7
- Yanase F, Cutuli SL, Naorungroj T, et al. A comparison of the hemodynamic effects of fluid bolus therapy with crystalloids vs. 4% albumin and vs. 20% albumin in patients after cardiac surgery. Heart Lung 2021; 50: 870-6
- Prowle JR, Kirwan CJ, Bellomo R. Fluid management for the prevention and attenuation of acute kidney injury. Nat Rev Nephrol 2014; 10: 37-47
- Wiedemann HP, Wheeler AP, Bernard GR, et al. Comparison of two fluid-management strategies in acute lung injury. N Engl J Med 2006; 354: 2564-75
- Tigabu BM, Davari M, Kebriaeezadeh A, et al. Fluid volume, fluid balance and patient outcome in severe sepsis and septic shock: a systematic review. J Crit Care 2018; 48: 153-9
- Bayer O, Reinhart K, Kohl M, et al. Effects of fluid resuscitation with synthetic colloids or crystalloids alone on shock reversal, fluid balance, and patient outcomes in patients with severe sepsis: a prospective sequential analysis. Crit Care Med 2012; 40: 2543-51
- Bayer O, Reinhart K, Sakr Y, et al. Renal effects of synthetic colloids and crystalloids in patients with severe sepsis: A prospective sequential comparison. Crit Care Med 2011; 39: 1335-42
- Myburgh JA, Finfer S, Bellomo R, et al. Hydroxyethyl starch or saline for fluid resuscitation in intensive care. N Engl J Med 2012; 367: 1901-11
- Perner A, Haase N, Guttormsen AB, et al. Hydroxyethyl starch 130/0.42 versus Ringer’s acetate in severe sepsis. N Engl J Med 2012; 367: 124-34
- The SSI, Finfer S, McEvoy S, et al. Impact of albumin compared to saline on organ function and mortality of patients with severe sepsis. Intensive Care Med 2011; 37: 86-96
- Finfer S, Bellomo R, Boyce N, et al. A comparison of albumin and saline for fluid resuscitation in the intensive care unit. N Engl J Med 2004; 350: 2247-56
- Vincent JL, Wilkes MM, Navickis RJ. Safety of human albumin — serious adverse events reported worldwide in 1998–2000. Br J Anaesth 2003; 91: 625-30
- Wiedermann CJ, Joannidis M. Albumin replacement in severe sepsis or septic shock. N Engl J Med 2014; 371: 83
- Caironi P, Tognoni G, Masson S, et al. Albumin replacement in patients with severe sepsis or septic shock. N Engl J Med 2014; 370: 1412-21
- Charpentier J, Mira JP. Efficacy and tolerance of hyperoncotic albumin administration in septic shock patients: the EARSS study. Intensive Care Med 2011; 37 (Suppl): S115
- Iguchi N, Kosaka J, Bertolini J, et al. Differential effects of isotonic and hypotonic 4% albumin solution on intracranial pressure and renal perfusion and function. Crit Care Resusc 2018; 20: 48-53
- Mårtensson J, Bihari S, Bannard-Smith J, et al. Small volume resuscitation with 20% albumin in intensive care: physiological effects: the SWIPE randomised clinical trial. Intensive Care Med 2018; 44: 1797-806
- Wigmore GJ, Anstey JR, St. John A, et al. 20% Human Albumin Solution Fluid Bolus Administration Therapy in Patients After Cardiac Surgery (the HAS FLAIR Study). J Cardiothorac Vasc Anesth 2019; 33: 2920-7
- Lewis SR, Pritchard MW, Evans DJW, et al. Colloids versus crystalloids for fluid resuscitation in critically ill people. Cochrane Database Syst Rev 2018; (8): CD000567
- Hanley C, Callum J, Karkouti K, et al. Albumin in adult cardiac surgery: a narrative review. Can J Anaesth 2021; 68: 1197-213
- Chan A-W, Tetzlaff JM, Altman DG, et al. SPIRIT 2013 statement: defining standard protocol items for clinical trials. Ann Intern Med 2013; 158: 200-7
- Schulz KF, Altman DG, Moher D. CONSORT 2010 statement: updated guidelines for reporting parallel group randomised trials. BMJ 2010; 340: c332
- ICH Harmonised Tripartite Guideline. Statistical principles for clinical trials. International Conference on Harmonisation E9 Expert Working Group. Stat Med 1999; 18: 1905-42
- Behring C. Australian product information: Albumex 20 (human albumin) — solution for intravenous infusion. CSL Behring, 2020. https://www.cslbehring.com.au/-/media/cslb-australia/documents/aus-pis-and-cmis/albumex-20-au-pi-1300.pdf? (viewed Oct 2)
- Behring C. Australian product information: Albumex 4 (human albumin) — solution for intravenous infusion. CSL Behring, 2020. https://labeling.cslbehring.com/PI/AU/Albumex/EN/Albumex-4-Product-Information.pdf? (viewed Oct 2022)
- Hammond NE, Taylor C, Saxena M, et al. Resuscitation fluid use in Australian and New Zealand Intensive Care Units between 2007 and 2013. Intensive Care Med 2015; 41: 1611-9
- Harris PA, Taylor R, Minor BL, et al. The REDCap consortium: building an international community of software platform partners. J Biomed Inform 2019; 95: 103208
- Harris PA, Taylor R, Thielke R, et al. Research electronic data capture (REDCap) — a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform 2009; 42: 377-81
- Bihari S, Prakash S, Potts S, et al. Addressing the inadvertent sodium and chloride burden in critically ill patients: a prospective before-and-after study in a tertiary mixed intensive care unit population. Crit Care Resusc 2018; 20: 285-93
- Delaney A, Angus DC, Bellomo R, et al. Bench-to-bedside review: the evaluation of complex interventions in critical care. Crit Care 2008; 12: 210
- Billah B, Huq MM, Smith JA, et al. AusSCORE II in predicting 30-day mortality after isolated coronary artery bypass grafting in Australia and New Zealand. J Thorac Cardiovasc Surg 2014; 148: 1850-5
- Lamontagne F, Richards-Belle A, Thomas K, et al. Effect of reduced exposure to vasopressors on 90-day mortality in older critically ill patients with vasodilatory hypotension: a randomized clinical trial. JAMA 2020; 323: 938-49
- Hicks P, Huckson S, Fenney E, et al. The financial cost of intensive care in Australia: a multicentre registry study. Med J Aust 2019; 211: 324-5
- Fujii T, Udy AA, Deane AM, et al. Vitamin C, Hydrocortisone and Thiamine in Patients with Septic Shock (VITAMINS) trial: study protocol and statistical analysis plan. Crit Care Resusc 2019; 21: 119-25
- Sevransky JE, Rothman RE, Hager DN, et al. Effect of vitamin C, thiamine, and hydrocortisone on ventilator- and vasopressor-free days in patients with sepsis: the VICTAS randomized clinical trial. JAMA 2021; 325: 742-50
- Fujii T, Luethi N, Young PJ, et al. Effect of vitamin C, hydrocortisone, and thiamine vs hydrocortisone alone on time alive and free of vasopressor support among patients with septic shock: the VITAMINS randomized clinical trial. JAMA 2020; 323: 423-31
- Khanna A, English SW, Wang XS, et al. Angiotensin II for the treatment of vasodilatory shock. N Engl J Med 2017; 377: 419-30
- Cook D, Lauzier F, Rocha MG, et al. Serious adverse events in academic critical care research. CMAJ 2008; 178: 1181-4
- Lehmann ELDAHJM. Nonparametrics: statistical methods based on ranks. Upper Saddle River, NJ: Prentice Hall; 1998
- DAMOCLES Study Group, NHS Health Technology Assessment Programme. A proposed charter for clinical trial data monitoring committees: helping them to do their job well. Lancet 2005; 365: 711-22
- Jennison C, Turnbull BW. Group sequential methods with applications to clinical trials. Boca Raton (FL): Chapman and Hall/CRC, 2000
- National Health and Medical Research Council, Australian Research Council, Universities Australia. National statement on ethical conduct in human research (2007) [updated 2018]. https://www.nhmrc.gov.au/about-us/publications/national-statement-ethical-conduct-human-research-2007-updated-2018#block-views-block-file-attachments-content-block-1 (viewed Oct 2022)
- Australian and New Zealand Intensive Care Society. ANZICS Clinical Trials Group — co-enrolment policy. https://www.anzics.com.au/wp-content/uploads/2018/09/ANZICS-CTG-Co-Enrolment_Policy-September-2015.pdf (viewed Oct 2022)
Adrenaline and vasopressin doses will be converted to the equivalent noradrenaline dose using an established conversion scale. 38, 39
The trial secondary outcomes are listed in Table 2. The additional process of care measures concerning fluid administration will be presented (Online Appendix).
In addition, the following nested studies are planned:
- haemodynamic profile of fluid bolus therapy using continuous haemodynamic monitoring;
- health economic evaluation; and
- biomarker assessment using baseline and 24-hour data relating to renal biomarkers.
Analysis and reporting of results
Data collection and management
Accuracy and consistency checks of collected data will be carried out by automatic validation, and by pre-specified and ad hoc checking by personnel at the coordinating centre. On-site or remote data monitoring will be performed to verify the data for the primary outcome of 30% of the patients enrolled into the study which will selected at random and stratified by group.
Statistical analysis plan
The sample size was calculated using pilot data from our single centre exploratory study. 20
Baseline characteristics and primary outcomes
Firstly, all data will be assessed for approximate normality and presented by treatment allocation. Summary statistics for categorical variables will be presented as frequency (%) and compared using χ2 tests for equal proportion. Continuous variables will be summarised as mean (SD) or median (interquartile range [IQR]) and initially compared using a Student t tests for normally distributed variables or Wilcoxon rank sum tests otherwise.
The primary outcome will be reported as the difference (95% confidence interval [CI]) between the intervention and comparator in their median (quantile = 0.5) hours of vasopressor treatment as returned by a simple quantile linear regression model incorporating adjustment for the trial sites as a random effect.
Subsequent sensitivity analyses maybe performed using covariates showing baseline imbalance (P < 0.1) and may also include age, sex, estimated 30-day postoperative mortality as determined by the European System for Cardiac Operative Risk Evaluation (EuroSCORE) II, and individual variables of the EuroSCORE-II risk model. Time to cessation of vasopressor therapy will be explored using Cox proportional hazards regression adjusting for trials sites as a random effect, with results reported as hazard ratio (95% CI) and also presented using Kaplan–Meier survival curves, with treatment comparison using log-rank tests.
In the present trial design, a patient death on or before day 7 may, by acting as a competing event, preclude observation of vasopressor cessation — the primary endpoint of interest. If such early deaths occur, exploratory analyses may assess according to treatment allocation:
- cumulative duration of vasopressor therapy in survivors to end of day 7;
- cumulative duration of vasopressor therapy-free time in survivors to end of day 7;
- cumulative duration of vasopressor therapy in patients who die before the end of day 7; and
- cumulative duration of vasopressor therapy-free time in patients who die before the end of day 7.
All main statistical analyses will be conducted on an intention-to-treat basis. Pre-specified exploratory analyses will be performed within two subgroups irrespective of evidence for an overall treatment effect: i) presence or absence of any vasopressor therapy at randomisation, and ii) pre-operative plasma albumin concentration dichotomised at the median of the pooled group albumin (g/L). A two-tailed P < 0.05 will be used to indicate statistical significance of the primary outcome, and there will be no formal adjustment of this statistical threshold for non-primary outcomes, which are all exploratory in nature.
No imputation will be undertaken for missing data. Rates for missing data will be reported in the Online Appendix.
An independent Data Safety Monitoring Board (DSMB), composed of an experienced clinical researcher and biostatistician without other connection to the HAS FLAIR-II trial, will operate under a charter based on the recommendations of the DAMOCLES Study Group (Online Appendix). 42
Presentation of outcome data
Approach to co-enrolment
Data sharing statement
Acknowledgements: All authors gave final approval of the version to be published and agreed to be accountable for all aspects of this work. The HAS FLAIR-II trial is supported by a grant from CSL Behring. Geoffrey Wigmore is supported by a National Health and Medical Research Council Postgraduate Scholarship. None of these funding organisations has contributed to the study design; collection, management, analysis and interpretation of data, writing of the report, or the decision to submit the report for publication.