INOX-ICU 2

Rationale

Depending on the duration of critical illness eventually all critically ill patients develop anaemia which may severely affect their recovery.¹  Severe anaemia is associated with a generalized decrease in oxygen carrying capacity and potentially ensuing multi-organ failure. Red cell transfusions are given to improve the oxygen carrying capacity. For a long time, transfusion trigger level of 7-8 g/dl has been used and adapted in clinical guidelines.^2-4 However, evidence is increasing that in some cases a haemoglobin trigger of 7-8g/dl may be too low and that an individualized red cell transfusion strategy may benefit critically ill patients.^5,6 Markers of hypoperfusion together with Hb values have been used to guide these blood transfusion decisions. However, there is no high-quality data supporting the use of these markers.^7,8 New studies have shown the potential of a protoporphyrin IX-triple state lifetime technique to measure mitochondrial oxygenation tension (mitoPO2) in vivo, which possibly is an early indicator of oxygen imbalance in the cell.^9,10  Recently, Römers et al. (2016) showed that mitoPO2 is a potential early indicator of the physiological limit of haemodilution and possibly a physiologic trigger for blood transfusion.¹¹ However, this potential has only been shown in animal models^12-14 and healthy volunteers.¹⁵ Consequently, this study is the first on mitoPO2’s clinical applicability in critically ill patients with anemia. The results of this study could further tailor transfusion strategies to the individual critical care patient.

Objectives

We have multiple objectives for this study, which are the following:
To determine the feasibility of using mitoPO2 and the variability of mitoPO2 measurements in critically ill intensive care unit patients who are about to receive a red cell transfusion. 
To describe the effects of red cell transfusion and the associated change in haemoglobin on mitoPO2 and on other physiologic measures of tissue oxygenation and oxygen balance 
To describe the association between mitoPO2 and vital organ functions.

Study design

A pilot study followed by a prospective multicentre cohort study.

Study population

The studied population consists of all adult patients with anaemia in the ICU in whom a central venous catheter is already in place and in whom a red cell transfusion is planned.

Study endpoints

The primary endpoint of this study is variability of mitoPO2 before and after red cell transfusion. This will be compared to traditional parameters used to measure tissue oxygenation and oxygen balance.

The secondary endpoints are the following:

• Value of mitoPO2 in predicting (ischemic) organ damage
• Association of mitoPO2 with the microcirculation
• Duration of mechanical ventilation
• Need for continuous renal replacement therapy
• Length of ICU-stay
• Length of hospital-stay
• ICU-mortality
• 90-day mortality

Research staff

M. Baysan, MD (PhD student and coordinating investigator) ^1,2,3,4
Prof. J.G. van der Bom, MD PhD ^1,2,3
M.S. Arbous, MD PhD ^3,4
Prof. N.P. Juffermans, MD PhD ⁵
E.G. Mik, MD PhD ⁶

1. Center for Clinical Transfusion Research, Sanquin Research, Leiden
2. Jon J van Rood Center for Clinical Transfusion Research, Sanquin-Leiden University Medical Center, Leiden 
3. Department of Clinical Epidemiology, Leiden University Medical Center, Leiden
4. Department of Intensive Care Medicine, Leiden University Medical Center, Leiden
5. Department of Intensive Care, Amsterdam Medical Center, Amsterdam
6. Department of Anaesthesiology, Erasmus Medical Center, Rotterdam

References

1. Corwin HL, Gettinger A, Pearl RG, et al. The CRIT Study: Anemia and blood transfusion in the critically ill--current clinical practice in the United States. Crit Care Med 2004;32:39-52.
2. Hebert PC, Carson JL. Transfusion threshold of 7 g per deciliter--the new normal. N Engl J Med 2014;371:1459-61. 
3. Chohan SS, McArdle F, McClelland DB, Mackenzie SJ, Walsh TS. Red cell transfusion practice following the transfusion requirements in critical care (TRICC) study: prospective observational cohort study in a large UK intensive care unit. Vox sanguinis 2003;84:211-8.
4. Retter A, Wyncoll D, Pearse R, et al. Guidelines on the management of anaemia and red cell transfusion in adult critically ill patients. British journal of haematology 2013;160:445-64.
5. Murphy GJ, Pike K, Rogers CA, et al. Liberal or restrictive transfusion after cardiac surgery. N Engl J Med 2015;372:997-1008.
6. Zheng Y, Lu C, Wei S, Li Y, Long L, Yin P. Association of red blood cell transfusion and in-hospital mortality in patients admitted to the intensive care unit: a systematic review and meta-analysis. Crit Care 2014;18:515.
7. Holst LB, Carson JL, Perner A. Should red blood cell transfusion be individualized? No. Intensive care medicine 2015;41:1977-9.
8. Vincent JL. Indications for blood transfusions: too complex to base on a single number? Annals of internal medicine 2012;157:71-2.
9. Mik EG. Special article: measuring mitochondrial oxygen tension: from basic principles to application in humans. Anesth Analg 2013;117:834-46.
10. Harms FA, Voorbeijtel WJ, Bodmer SI, Raat NJ, Mik EG. Cutaneous respirometry by dynamic measurement of mitochondrial oxygen tension for monitoring mitochondrial function in vivo. Mitochondrion 2013;13:507-14.
11. Romers LH, Bakker C, Dollee N, et al. Cutaneous Mitochondrial PO2, but Not Tissue Oxygen Saturation, Is an Early Indicator of the Physiologic Limit of Hemodilution in the Pig. Anesthesiology 2016;125:124-32.
12. Harms FA, Bodmer SI, Raat NJ, Mik EG. Non-invasive monitoring of mitochondrial oxygenation and respiration in critical illness using a novel technique. Crit Care 2015;19:343.
13. Mik EG, Johannes T, Zuurbier CJ, et al. In vivo mitochondrial oxygen tension measured by a delayed fluorescence lifetime technique. Biophys J 2008;95:3977-90.
14. Mik EG, Ince C, Eerbeek O, et al. Mitochondrial oxygen tension within the heart. J Mol Cell Cardiol 2009;46:943-51.
15. Harms F, Stolker RJ, Mik E. Cutaneous Respirometry as Novel Technique to Monitor Mitochondrial Function: A Feasibility Study in Healthy Volunteers. PLoS One 2016;11:e0159544.