The document discusses a study on goal-directed hemodynamic therapy (GDT) aimed at improving outcomes for high-risk surgical patients. It highlights the need for advanced monitoring and the variability in GDT protocols, as well as the design and progress of the ongoing trial with interim results indicating a high occurrence of complications. The authors conclude that GDT can be beneficial for peri-operative risk management, necessitating more large-scale, multicenter trials.

1. What happened in the meantime?
Sandra Funcke, MD, DESA
9th IFAD – Valencia October 26th, 2019
Clinic for Anesthesiology and Intensive Care Medicine, University Medical
Center Hamburg-Eppendorf, Hamburg, Germany

2. Acknowledgements/COI
“This trial is supported by an unrestricted research grant by the Getinge Group,
PULSION Medical Systems SE, Hans-Riedl Str. 2, 85622 Feldkirchen, Germany. The
funders have no role in the content, decision to publish, or preparation of the
manuscript. None of the clinical investigators enrolling patients have received any
honorarium for participating in the study.”
We thank Frank Ponndorf (MedSurv GmbH, Nidderau, Germany) for setup and continuous care of the
eCRF. Further, we thank EuroQuol for providing us the quality of life questionnaire.

3. Why use peri-operative goal-directed hemodynamic therapy ?
• Mortality rate of 1-4%1 peri-operatively, in high-risk surgical
procedures/patients up to 7.6%2
• Optimization of global hemodynamics to improve oxygen delivery and organ
perfusion pressure
• Protocolized treatment strategy: titrate fluids, vasopressors and inotropes
(no consent)
• Advanced hemodynamic monitoring needed (blood pressure ≠ blood flow):
dynamic preload variables and variables of blood flow (CO/CI, SV)
• Problem: GDT poorly defined - still searching for the “optimal” treatment
protocol  poorly adopted in daily clinical routine
1 EuSoS. Lancet. 2012 Sep 22;380(9847):1059-65. ; 2 Hamilton et al. Anesth Analg. 2011 Jun;112(6):1392-402.

4. Extract of previous trials: why another study on GDT?
• Shoemaker 1988 (Chest): CI-monitoring (PAC) per protocol in high-risk
patients reduced mortality, complication rate, days in hospital and costs
• Rivers 2001 (NEJM): early GDT in severe sepsis / septic shock lowered in-
hospital mortality from 46.5% to 30.5%
• Smaller RCTs in different fields of surgery – favorable results of GDT
• Pearse (OPTIMISE) 2014 (JAMA), Calco-Vecino (FEDORA) 2018 (BJA)
• Meta-analyses (Cecconi 2013 (Crit Care), Michard 2017 (BJA), Chong 2018
(EJA), Kendrick J (Anaesthesiol Clin Pharmacol 2019 )): morbidity and
mortality reduced, BUT….

5. Kendrick JB, Kaye AD, Tong Y, Belani K, Urman RD, Hoffman C, et al. Goal-directed fluid
therapy in the perioperative setting. J Anaesthesiol Clin Pharmacol 2019;35:S29-34.
… but: high rate of heterogeneity (type of surgery, devices, protocols)

6. Chong et al. Eur J Anaesthesiol 2018; 35:469–483
Chong EJA 2018: Meta-analysis
… but: low quality of evidence (blinding), heterogeneity (type of surgery, devices,
protocols)  larger trials with more patients needed (e.g. OPTIMISE II)

8. Patient
enrolment
Randomization
Intervention Group Control Group
Intraoperative
Therapy according
to iGDT Algorithm
Intraoperative
Therapy according
to Local Care
Primary endpoint
Composite of at least one severe or moderate
complication and mortality on day 28
Secondary endpoint
Morbidity on day 1, 3, 5, 7 and 28
Length of Intensive Care Unit (ICU) and Hospital Stay
Days Alive and Free of Mechanical Ventilation at 7 Days and 28 Days
Days Alive and Free of Vasopressor Therapy at 7 Days and 28 Days
Days Alive and Free of Renal Replacement Therapy at 7 Days and 28 Days
Quality of life and mortality at 6 Months
vs.

9. Key inclusion criteria:
- patients undergoing major abdominal surgery
(visceral, gynaecological, urological) with laparotomy
- duration of surgery with an expected minimum of 120 minutes
- an expected requirement of fluid therapy of more than 2 litres
- patients having a probability for any postoperative complications of
≥10% assessed by the ACS-NSQUIP risk calculator
Key exclusion criteria:
- primarily vascular surgery
- emergency surgery
- laparoscopic surgical approach
- patients not having sinus rythm
- severe cardiac valve pathologies, EF <30%
- sepsis/septic shock
- palliative situation

10. Control group
• Treatment according to „local care“ (ECG, NIBP, SpO2, etCO2 mandatory)
• Instrumentation according to local standard
• Fluid- and catecholamine-management at the discretion of the treating
clinician
• HR < 100 bpm
• MAP > 65 mmHg
• SpO2 > 94%
• Body core temperature > 36 degree Celsius

11. Intervention group
 targeting the individual optimal cardiac index (CI)
… pulse-contour analysis (ProAQT© device; Pulsion Medical Systems, Feldkirchen,
Germany), need of fluids assessed based on pulse pressure variation (PPV)

12. Intervention group: individual optimal CI

13. Intervention group: individual optimal CI

14. OPTIMISE vs .

15. Primary endpoint
Composite of at least one severe or
moderate complication and mortality
on day 28
Complications are defined by:

16. Single organ outcome measures
• Myocardial infarction
• Myocardial injury after non-cardiac
surgery
• Pneumonia
• Paralytic ileus
• Postoperative haemorrhage
• Pulmonary embolism
• Stroke
• Surgical site infection, superficial
• Surgical site infection, deep
• Surgical site infection, organ/space
• Urinary tract infection
• Acute kidney injury
• Acute respiratory distress
syndrome
• Anastomotic breakdown
• Arrhythmia
• Cardiac arrest
• Cardiogenic pulmonary oedema
• Deep vein thrombosis
• Delirium
• Gastrointestinal bleed
• Infection, source uncertain
• Bloodstream infection
(confirmed)

17. Severity grading integrated in the definition: AKI, ARDS, Delirium
Severity Grading

18. Binary outcome: Cardiac arrest; MINS
All others:
Severity Grading

19. Prof. M. Sander
Dr. C. Koch
+team
Dr. B. Neukirch
Dr. A. Zitzmann
Prof. T. Mencke +team
Prof. D. Reuter
Dr. S. Haas
Prof. B. Saugel
Dr. S. Funcke
Dr. O. Díaz Cambronero +team
Anabel Marquis, Javier Belda
Dra. V. Moral, R. Acosta, Dr. G. Azparren
+team

20. To date…
• 4 centers participating
• Interimanalysis (190 of planned 380 patients):
 all patients received time point of primary endpoint
 monitoring visits to check Single Organ Outcome Failures
 Occurrence of primary endpoint: n=96 (59.5%), varies between hospitals,
Mortality 4.7%
Center iGDT Ctrl. Total (patients)
Rostock (D) 13 13 26
Gießen (D) 21 25 46
Valencia (ES) 26 27 53
Barcelona (ES) 29 36 65
89 101 190

21. Conclusion:
• GDT beneficial for patients with high peri-operative risk (low
flow situations: “We cannot treat what we don’t detect”.)
• Saugel 2019 (BJA): The ‘5 Ts’ – target population, timing of the
intervention, type of intervention, target variable, target value
• Define, implement and optimize GDT protocols (guideline)
• Need for more large, multicenter trials
• iPegasus:
 Individualizing the parameters of GDT  maximize tissue oxygen delivery
 Interimanalysis - another 190 patients planned

22. Prof. M. Sander
Dr. C. Koch
+team
Dr. B. Neukirch
Dr. A. Zitzmann
Prof. T. Mencke +team
Prof. D. Reuter Dr. S. Haas
Prof. B. Saugel Dr. S. Funcke
Dr. O. Díaz Cambronero +team
Anabel Marquis, Javier Belda
Dra. V. Moral, R. Acosta, Dr. G. Azparren
+team
Many thanks to our collaborators for all the hard work!

23. Universtiy Medical Center Hamburg-Eppendorf
Martinistraße 52
D-20246 Hamburg
Dr. med. Sandra Funcke, DESA
s.funcke@uke.de
Many thanks to our collaborators for all the hard work!

24. Sample Size Calculation
Incidence of primary endpoint in the intervention group: 33%
Incidence of primary endpoint in the control group : 48%
Maximum
Test significance level, a 0.0500
1 or 2 sided test? 2
Group 1 proportion, p1 0.48
Group 2 proportion, p2 0.33
Odds ratio, y = p2 (1 - p1) / [p1 (1 - p2)] 0.5336
Power ( % ) 80.00
n per group 167
Estimated drop-out rate of 10% and
exclusion of the first 2 patients per centre
(n=6)
n=380 Patienten

25. Quality of life – EuroQol