1. Goal directed therapy Ben Creagh-Brown March 2004

2. Introduction Failure of oxygen supply to meet metabolic needs is the feature common to all forms of circulatory failure or "shock". Prevention, early identification, and correction of tissue hypoxia are therefore necessary skills in managing the critically ill patient and this requires an understanding of oxygen transport, delivery, and consumption.

3. To improve outcome after surgery and in critically ill patients there is a strategy called: “goal directed therapy” “haemodynamic optimisation” “pre-optimisation” if done prior to an operation

4. This strategy involves: Using cardiac output monitoring (or a surrogate) in addition to standard critical care monitoring Taking the information from this and calculating derived variables including global oxygen delivery (not always) Modifying the haemodynamic state with the aim of increasing global oxygen delivery, often to normal beyond normal = supra-physiological. This could be with fluids, inotropes and/or blood transfusions.

5. Recognition of inadequate oxygen delivery No signs/symptoms Progressive metabolic acidosis Hyperlactataemia Falling mixed venous oxygen saturation (SvO 2 ) Organ specific features: Oliguria Impaired level of consciousness / confusion

6. Hyperlactataemia (>2 mmol/l) may be caused by either increased production or reduced hepatic metabolism. Both mechanisms frequently apply in the critically ill patient since a marked reduction in DO 2 produces global tissue ischaemia and impairs liver function.

7. What is Global oxygen delivery? Global oxygen delivery = DO 2 = The total amount of oxygen delivered to the tissues per minute irrespective of the distribution of blood flow How is it calculated? DO 2 is the product of cardiac output (Qt) and arterial oxygen content (CaO 2 )

8. Calculations Cardiac output (Qt) is Heart Rate X Stroke Volume (ml), (ml/min) Arterial Oxygen content (CaO 2 ) is Saturation of Hb (%) X Concentration of Hb (g/l) X Constant

9. Oxygen carrying Each gram of haemoglobin can carry 1.31 ml of oxygen when it is fully saturated. Therefore every litre of blood with a Hb concentration of 15g/dl can carry about 200 mls of oxygen when fully saturated (occupied) with oxygen (PO2 >100 mmHg). At this PO2 only 3 ml of oxygen will dissolve in every litre of plasma

10. A normal person Stroke Volume80 ml 70-100 ml HR70 /min Cardiac output (Qt) Qt = 70 bpm X 80 ml = 5600 ml = 5.6l/min

11. Oxygen content of blood Hb13.0g/dl FiO20.21 PaO213.0kPa SaO297% CaO2 = 10 [ (Hb x SaO2 x 1.36) + (PaO2 x 0.023)] = 10 [ (13.0 x 0.97 x 1.36) + (13.0 x 0.023)] = 10 [( 17.1496 + 0.299 )] = 174.486 ml O 2 / l blood

12. DO 2 and DO 2 I DO2 = Qt xCaO2 =5600 x174.5 = 977 l O2/min Height 1.6 m, weight 80 kg Body Surface Area = √( (cm*kg)/3600 ) = 1.8 m 2 DO2I=DO2 / BSA =977 / 1.8 =542.7 l/min/m 2

13. Oxygen delivery index DO 2 I Normal range = 500 to 600 ml/min/m 2 Global oxygen delivery is a product of cardiac output, concentration of haemoglobin and arterial saturation of blood (and therefore oxygenation).

14. Shorter formulae DO 2 I (mL/min per m 2 ) = CI (L/min per m 2 ) x SaO 2 (%) x Hb (g/L) x 0.0134 VO 2 I (mL/min per m 2 ) = CI (L/min per m 2 ) x (SaO 2 - SvO 2 ) x Hb (g/L) x 0.0134 Ignore effect of O 2 dissolved in plasma

15. D O 2 (% change) FIO 2 PaO 2 (kPa) SaO 2 (%) Hb (g/l) Dissolved O 2 (ml/l) CaO 2 (ml/l) Qt (l/min) DO 2 (ml/min) % change in DO 2 Normal*0.2113.0961303.01705.39000 Patient0.216.075701.4724.0288– 68 ↑FIO 2 0.359.092702.1884.0352+ 22 ↑↑FIO 2 0.6016.598703.8964.0384+ 9 ↑Hb0.6016.5981053.81424.0568+48 ↑Qt0.6016.5981053.81426.0852+50

16. Things to note from table Global DO 2 depends on oxygen saturation rather than partial pressure and there is therefore little extra benefit in increasing PaO2 above 9 kPa since, due to the sigmoid shape of the oxyhaemoglobin dissociation curve, over 90% of haemoglobin (Hb) is already saturated with oxygen at that level. Although blood transfusion to polycythaemic levels might seem an appropriate way to increase DO 2, blood viscosity increases markedly above 100 g/l. This impairs flow and oxygen delivery, particularly in smaller vessels and when the perfusion pressure is reduced, and will therefore exacerbate tissue hypoxia.

17. How can we measure oxygen delivery and consumption? Approximately 250 ml of oxygen are used every minute by a conscious resting person and therefore about 25% of the arterial oxygen is used every minute. The haemoglobin in mixed venous blood is about 70% saturated (95% less 25%). Global oxygen delivery is DO 2, Global oxygen consumption is VO 2 measures the total amount of oxygen consumed by the tissues per minute. It can be measured directly from inspired and mixed expired oxygen concentrations and expired minute volume, or derived from the cardiac output (Qt) and arterial and venous oxygen contents: VO 2 = Qt x (CaO 2 – CvO 2 ) Directly measured VO2 is slightly greater than the derived value that does not include alveolar oxygen consumption.

18. Relationship between oxygen delivery and consumption

19. Explanation The flat portion of the biphasic relationship between oxygen consumption (VO2) and oxygen delivery (DO2) is associated with aerobic metabolism = B to C is where a normal person should be – the amount of oxygen consumed is more than adequately supplied. If more is supplied the consumption does not increase. NB: If our example the normal person had a value of 977 ml/min oxygen delivery. O 2 ER is the oxygen extraction ratio and is the ratio of oxygen consumed to oxygen delivered i.e. VO2/DO2. A normal adult undertaking routine activities VO2 is approximately 250ml/min and would equate to an OER of ~25% which could increase to 80% during maximal exercise. The oxygen not extracted by the tissues returns to the lungs and the mixed venous saturation (SvO2) measured in the PA represents the pooled venous saturations of all organs. Provided that microcirculation and cellular metabolism is intact a value of 70% indicates that global DO 2 is adequate. The sharply sloped portion (A to B, (termed pathologic supply dependence) is associated with tissue hypoxia, anaerobic metabolism, and the development of multiple organ dysfunction

20. How critical illness affects oxygenation The shape of this interdependence is thought to be altered in critical illness particularly sepsis. E to F. There is less of a plateau i.e. the more O 2 you give the more is used, or that there is always a degree of pathologically dependent supply. D to E. The slope of maximum OER is reduced – reflecting the reduced ability of tissues to extract oxygen.

21. Why target oxygen delivery? The presence of a degree of pathologically dependent supply provided the scientific basis for increasing the oxygen delivery as much as possible Shortcomings in the standard approach of assessing shock: physical signs, vitals, CVP, and UO considered together cannot detect persistent global tissue hypoxia.

22. What evidence is there for the benefit of targeting DO 2 ?

23. 1973 Shoemaker’s original study defined “survivor characteristics” Archives of Surgery 106:630-6 Haemodynamic and oxygen transport variables were monitored preoperatively, during surgery, and in the immediate postoperative period in 708 high-risk critically ill surgical patients. The temporal patterns of the survivors' values were compared with the patterns of those who died. The non-survivors were found to have relatively normal values for cardiac output, oxygen delivery DO2, and oxygen consumption VO2, while survivors had markedly increased values for these variables

24. 1988 Shoemaker’s intervention study in surgical patients Chest 94:1176-86 The survivors developed a pattern of supranormal cardiac index, DO2, and VO2. The hypothesis is that if high-risk patients are prophylactically driven to the survival pattern with early aggressive therapy that optimizes cardiac output, DO2, and VO2, there will be improved outcome. In a prospective preoperatively randomized trial of this hypothesis, each high-risk patient was identified preoperatively and randomized to one of three groups: the central venous catheter; the pulmonary artery catheter with normal values as the goal of therapy; the pulmonary artery catheter protocol group with supranormal values as the goal.

25. Continued… Pulmonary artery supranormal group results: Mortality was significantly reduced from 32 per cent to 4 per cent (p <0.02) Significant reduction of 67 per cent in ventilator days Reduction of 30 per cent in intensive care unit and hospital days Reduction of 25 per cent in the cost of treatment Of interest was a group of high-risk patients who were not considered to be sick enough to need invasive monitoring. This ‘non-randomized group' had the highest mortality and highest percentage of organ failure; ironically, 60 per cent had a pulmonary artery catheter placed postoperatively after they developed a life-threatening postoperative cardiorespiratory event. However, placement of the pulmonary artery catheter at this time did not improve the overall group mortality. This suggests that the pulmonary artery catheter can prevent but is not able to reverse lethal organ failure

26. Between 1988 and 1994 there were many studies on the use of GDT in various settings. Mixed results Common confounding factors: 1. Ignoring the mathematical linkage between DO2 and VO2 if derived from same observations (i.e. VO2 not measured but estimated using the reverse Fick principle) 2. Ignoring the physiological linkage between giving inotropes that increase both DO2 and VO2.

27. 1993 Owen Boyd at St George’s 107 high risk surgical patients Patients were randomly assigned to: control group (n=54) standard perioperative care protocol group (n=53) that, in addition, had deliberate increase of oxygen delivery index to greater than 600 mL/min per square meter by use of dopexamine hydrochloride infusion

28. Results 75% reduction in mortality (5.7% vs 22.2%; P=.015) Halving of the mean (+- SEM) number of complications per patient (0.68 (+- 0.16) vs 1.35 (+- 0.20); P=.008) in patients randomized to the protocol group Small study as stopped early as difference so significant. Control group was partially optimised.

29. NEJM 1994 and 1995 Two large randomised controlled trials showed no benefit of GDT in established shock. Also showed that those who are unable to increase their DO 2 either spontaneously or when pushed have a particularly poor prognosis – poor physiological reserve.

30. 1999 BMJ Wilson and Woods Pre operative optimisation in York RCT double blind 138 High risk surgical candidates Using inotropes to increase DO 2, compared adrenaline with dopexamine 3/92 (3%) pre-optimised patients died compared with 8/46 controls (17%) (P = 0.007). Dopexamine reduced inpatient stay

31. 2001 Emanuel Rivers’ Use of goal directed therapy early and aggressively in the management of severe sepsis[i] Early goal directed therapy in the treatment of severe sepsis and septic shock, Emanuel Rivers NEJM 2001;345:1368-77[i] Included: SIRS criteria and SBP 4. 263 patients, randomly assigned either to standard or EGDT Standard was CVP, Art line, hourly UO EGDT was as standard plus the use of an ScvO2 monitor Treatment protocol for EGDT: CVP<8 – fluids MAP <65 – Choice of vasoconstrictor ScvO2 30% If still <70% then add in dobutamine at 2.5mcg/kg/min and titrate. Only met goals and spent 6 hrs in ER went to ITU and ITU staff blinded to treatment received. ER docs had no further input.

32. Detroit’s results Results In hospital mortality for standard 46.5% down to 30.5% for EGDT Shorter in patient stay (for those who survived) 18.4 std and 14.6 EGDT Discussion Gave less fluid overall but more early in first few hours. More of them received inotropes and blood early

33. Summary 1. Pre operative optimisation in high risk patients reduces mortality 2. Restoration of global oxygen delivery is an important goal in early resuscitation but thereafter does not improve survival and may be harmful. 3. Microcirculatory, tissue diffusion, and cellular factors influence the oxygen status of the cell and global measurements may fail to identify local tissue hypoxaemia 4. Supranormal levels of oxygen delivery cannot compensate for diffusion problems between capillary and cell, nor for metabolic failure within the cell. 5. Strategies to reduce metabolic rate to improve tissue oxygenation should be considered. 6. SvO2 or ScvO2 can be used as surrogates of cardiac output

34. References Wilson J, Woods J, et al Reducing the risk of major elective surgery: a randomised controlled trial of preoperative optimisation of oxygen delivery. BMJ 1999;31:1099-103 Gattinoni L, Brazzi L, Pelosi P, et al, A trial of goal-orientated hemodynamic therapy in critically ill patients NEJM 1995 333:1025-1032 Hayes MA, Timmins AC, Yau E, Palazzo M, Hinds CJ, and Watson D, Elevation of Systemic Oxygen Delivery in the Treatment of Critically Ill Patients NEJM 1994 330:1717-1722 Boyd O, Grounds RM, Bennett DE, A Randomized Clinical Trial of the Effect of Deliberate Perioperative Increase of Oxygen Delivery on Mortality in High-Risk Surgical Patients JAMA 1993;270:2699-2707 Rivers E et al., Early goal directed therapy in the treatment of severe sepsis and septic shock, NEJM 2001;345:1368-77