The Journal of TRAUMA威 Injury, Infection, and Critical Care

Using Transcutaneous Oxygen Pressure Measurements as Selection Criteria for Activated Protein C Use Alyssa D. Chapital, MD, MS, Mihae Yu, MD, Hao Chih Ho, MD, John Wang, MD, Wega Koss, MD, and Danny M. Takanishi, Jr., MD Background: Limited resources and the expense of Activated Protein C (APC) (drotrecogin alfa) may contribute to the reluctance to utilize this drug in sepsis. Employing the PROWESS criteria resulted in absolute reduction in 28-day mortality of 6.1%, representing a relative risk reduction of 19.4%. Additional patient categorization and selection may lead to less frequent drug use with the same survival advantage. We used transcutaneous partial pressure of oxygen (PtcO2) as an indicator of microcirculatory perfusion to identify which septic patients may benefit from APC. Methods: Nineteen patients consecutively admitted with severe sepsis or septic

shock that fulfilled the PROWESS criteria for APC treatment. APC was administered to patients with the PROWESS selection criteria, only if the PtcO2 information demonstrated tissue ischemia. Results: Nineteen patients met the PROWESS criteria. Ten patients demonstrated poor tissue perfusion using PtcO2 monitors and received APC. Nine patients had adequate tissue perfusion and did not receive APC. There were no differences in age, gender, APACHE II scores, lactate levels, or organ failure between the two groups. The 10 patients who received APC had a mortality of 3 of 10 (30%). The survivors of this group uniformly converted to PtcO2 values consistent with sur-

vival within 12 hours to 24 hours of drug administration. The nine patients who did not receive APC had a mortality of 2 of 9 (22%), not statistically significant from those who received the drug ( p ⴝ 0.89). Conclusion: Withholding APC did not result in an increase in mortality from severe sepsis in those patients who demonstrated adequate PtcO2 values. The transcutaneous oxygen measurement may be a useful adjuvant in addition to the other selection criteria for better identification of patients who may benefit from APC. Key Words: Transcutaneous oxygen, Activated protein C, Drotrecogin alfa, Sepsis, Shock, Perfusion. J Trauma. 2008;65:30 –33.

T

he PROWESS trial was a prospective, randomized, blinded study of severely septic patients treated with drotrecogin alfa, i.e., recombinant human Activated Protein C (APC).1 APC is an endogenous antithrombotic and profibrinolytic agent that also has anti-inflammatory qualities. Microvascular occlusion may be prevented or reversed resulting in improved peripheral blood flow with less organ failure. The PROWESS study demonstrated a statistically significant reduction in mortality from 30.8% in the placebo group to 24.7% in the drotrecogin alfa treated group.1 An objective measurement of microvascular blood flow in response to APC treatment has been recently demonstrated utilizing orthogonal polarization spectral imaging of the sublingual microcirculation.2 However, this technology is currently not readily available in most hospitals.

Submitted for publication December 8, 2006. Accepted for publication May 9, 2007. Copyright © 2008 by Lippincott Williams & Wilkins From the Department of Surgery, University of Hawaii (A.D.C., M.Y., H.C.H., J.W., W.K., D.M.T.), John A. Burns School of Medicine, Honolulu, Hawaii; and Queen’s Medical Center (A.D.C., M.Y., H.C.H., W.K., D.M.T.), Honolulu, Hawaii. Address for reprints: Alyssa D. Chapital, MD, Department of Critical Care Medicine, 5777 East Mayo Blvd, Phoenix, AZ 85054; email: chapital. [email protected]. DOI: 10.1097/TA.0b013e3180eeab28

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Our group reported a method to detect early shock using transcutaneous partial pressure of oxygen (PtcO2) utilizing equipment accessible in the majority large centers. This method of assessing microvascular perfusion relies on the physiologic response of the skin to stimuli.3 The skin is the first organ to vasoconstrict in shock and the last to reperfuse with resuscitation.4,5 Transcutaneous pressure of oxygen correlates with PaO2 and FIO2 in nonshock states, but in shock situations, PtcO2 mirrors changes in cardiac output and oxygen delivery with minimum response to increasing FIO2. The discrepancy between PtcO2 and PaO2 was initially thought to be failure of technology but proved to be a valuable marker of early shock and poor peripheral tissue oxygenation as demonstrated in both animal studies4,6 and human subjects.5,7–13 This lack of response to a high FIO2 (called the Oxygen Challenge test) has been studied with invasive subcutaneous pO2 monitors and is related to poor outcome.14 –16 Our group reported that an Oxygen Challenge test with a PtcO2 increase of ⱕ21 mm Hg in response to an FIO2 of 1.0 to be associated with a 100% mortality.3 This study investigated the utility of the Oxygen Challenge test to refine the selection criteria for APC administration.

PATIENTS AND METHODS The Institutional Review Board approved the study. Patients sequentially admitted to the surgical intensive care unit, fulfilling the criteria of severe sepsis or septic shock and unstable enough to require a pulmonary artery catheter (PAC) July 2008

Transcutaneous Oxygen Pressure Measurements for APC Use were enrolled. Informed consent was obtained from the patient or the patient’s surrogate. Time of study initiation was identified as time of PAC insertion. All patients were treated to a systolic blood pressure ⱖ100 mm Hg, urine output of ⬎0.5 mL/kg/h, decreasing lactic acid with resuscitation, and mixed venous oxygen saturation of ⱖ70%. The goal was to resuscitate patients by 24 hours of PAC insertion. Resuscitation consisted of optimizing preload using crystalloid infusion in increments of 250 mL to 500 mL and/or red blood cell transfusion if hemoglobin was less than 10 g/dL. Norepinephrine or epinephrine was started at 1 ␮g/min and titrated to desired blood pressure if the patient was hypotensive despite adequate preload. Dobutamine (2–5 ␮g/ kg/min) or milrinone (starting at 0.375 ␮g/kg/min) titrated to desired cardiac index was started if inotropic support was needed. Afterload reduction was added if systemic vascular resistance index was elevated. Diuretics were given if pulmonary artery occlusion pressure was ⱖ18 mm Hg and clinical signs of hypervolemia were present. A transcutaneous probe (TCM3 Transcutaneous Oxygen or Carbon Dioxide Monitoring System, D280 combined electrode, Radiometer, Copenhagen, Denmark) was placed on the anterior chest of the patient after calibration. A baseline PtcO2 value on current FIO2 settings was obtained after a 10 minute to 15 minute equilibration time. The FIO2 was then increased to 1.0. After 5 minutes, the new PtcO2 value was recorded. The difference between the two PtcO2 values was defined as the Oxygen Challenge test. The Oxygen Challenge test was performed at the time of study entry and at 24 hours after resuscitation. This test was not performed if the FIO2 was ⬎0.80. A positive Oxygen Challenge test was defined as ⱖ40 mm Hg rise in PtcO2 on FIO2 of 1.0 and a baseline ⱖ30 mm Hg. Although our prior study identified the survival value of the Oxygen challenge test to be ⬎21 mm Hg at 24 hours after resuscitation, the lowest value associated with survival and no new organ failure development was 40 mm Hg. The lowest baseline PtcO2 value associated with survival was 28 mm Hg.3 The 30 mm Hg value chosen as an acceptable baseline PtcO2 is consistent with reported PtcO2 values of ⬍25 mm Hg as reflecting a 50% decrease in oxygen consumption and preceding cardiac arrest.5 A value of 40 mm Hg was identified to be a critical pO2 value in subcutaneous tissue microcirculation.15 A negative oxygen challenge test (OCT) was defined as a baseline PtcO2 value less than 30 mm Hg and/or an OCT value of less than 40 mm Hg. Patients who met the PROWESS criteria and demonstrated a negative Oxygen Challenge test after 24 hours of resuscitation received drotrecogin alfa. Those with a positive Oxygen Challenge test at 24 hours after resuscitation did not receive drotrecogin alfa. Descriptive statistics was used to summarize the patient characteristics (means and percentages for categorical data, means, and standard deviations for continuous data). Continuous data were compared using the student’s t test and Volume 65 • Number 1

analysis of variance. Discrete data were analyzed using Chisquare evaluation. A p value of less than 0.05% and 95% confidence interval was considered significant.

RESULTS A total of 21 patients met the PROWESS criteria for APC. There were two patients who did not receive drotrecogin alfa because of physician preference and family refusal. Both patients died of multisystem organ failure and were not included in the analysis. Of the remaining 19 patients, 9 had a positive Oxygen Challenge test and did not receive APC. Ten patients demonstrated negative test values and received APC treatment. There were no differences in the patient demographics or vasopressor requirements (Table 1). The mortality rate in patients with a negative Oxygen Challenge test who received drotrecogin alfa was 3 of 10, whereas the mortality in those patients with a positive Oxygen Challenge test without drotrecogin treatment was 2 of 9 ( p ⫽ 0.89). In the 10 patients that had an initial negative Oxygen Challenge test value, 7 converted to a positive OCT value after receiving APC. All seven of these patients survived. The three patients that did not transform from a negative to a positive Oxygen Challenge test after treatment died of multisystem organ failure. In the group of nine patients with positive Oxygen Challenge test who did not receive APC, the two deaths were from a cardiac arrest and withdrawal of life support by the family despite clinical improvement (n ⫽ 2).

Table 1 Patient Demographics and Treatment

Age (yrs) Male:female APACHE II Organ failure at study entry Source of sepsis Thoracic n ⫽ 1 Soft tissue n ⫽ 3 Renal n ⫽ 1 Thoracic n ⫽ 2 Soft tissue n ⫽ 1 Renal n ⫽ 1 Vasopressor (number of patients) Lactate level at study entry Mortality Cause of death

Oxygen Challenge Test ⬍40 mm Hg, N ⫽ 10

Oxygen Challenge Test ⱖ40 mm Hg, N⫽9

p

58.1 ⫾ 9.8 6:4 23.1 ⫾ 2.8 2.5 ⫾ 1.2

61.3 ⫾ 19.6 4:5 20.5 ⫾ 3.2 1.9 ⫾ 1.1

0.67 0.83 0.08 0.27

7 of 10

6 of 9

0.74

3.1 ⫾ 1.8

2.7 ⫾ 1.8

0.64

2 of 9 1 from cardiac arrest Withdrew life support (n ⫽ 1)

0.89

Abdominal n ⫽ 4 Abdominal n ⫽ 6

3 of 10 All from multisystem organ failure

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The Journal of TRAUMA威 Injury, Infection, and Critical Care DISCUSSION The addition of APC introduced a new era in sepsis treatment.1 Despite food and drug administration (FDA) support, there has been some hesitancy accepting this drug possibly because of limited resources.17,18 Our goal was to utilize an objective marker of tissue hypoperfusion to further select patients from the original PROWESS criteria. Although this preliminary study is small, the Oxygen Challenge test allowed us to decrease drotrecogin alfa use by 50% without resulting in a higher mortality rate. There were no statistically significant differences between those with an initial positive or negative test in APACHE II scores, the cause of sepsis, lactate levels, vasopressor requirement or the number of initial organ failure. The survivors in the group of patients that received APC all converted from negative to positive Oxygen Challenge test within 12 hours to 24 hours of initiating the drug. The three patients who did not convert to a positive OCT died. This could represent the improvement in microcirculatory perfusion by the antithrombotic, anti-inflammatory, and fibrinolytic effects of APC. De Backer and colleagues have visually demonstrated opening up of capillaries with drotrecogin alfa.2 This enhancement may translate into a reduction of organ failure and cellular death. The FDA advocates APC for patients who have APACHE II scores ⱖ25.17 The use of an outcome prediction score to analyze the need for therapy is controversial.19 It is questionable whether these scores are applicable in all patient populations, as the surgical subgroup analysis revealed an average APACHE II of 23.20 There is also no precedent for using APACHE II for novel therapies.21 Because of underestimation of mortality in surgical patients22,23 withholding drotrecogin alfa based on APACHE II alone may exclude patients who might benefit from treatment. Even supporters of the FDA recommendations recognize that this “hypothesis of exclusive benefit has not been proven.”18 This is in contradistinction that APC has not been demonstrated with certainty to benefit those patients with an APACHE II score of less than 25.24 It is with this ambiguity that we sought for some impartial measure to assist our decision-making. Our patients had lower APACHE II scores than recommended for APC use as the majority had therapy initiated from the emergency room, operating rooms or another hospital. The severity of illness is reflected in other variables such as the number of organ failure and the need for vasopressor support. Our patient group is similar to the surgical cohort analysis performed from the PROWESS study that revealed an average APACHE II score of 23.5. The transcutaneous monitor was introduced in the 1970s as a method to continuously monitor the asphyxiated newborn. Even in the initial description, it was suggested that the monitor would increase our knowledge about the action of different drugs.25 Initial studies showed that PaO2 did not correlate with the PtcO2 in critically ill adults. This was postulated to occur because of shock, occult, or clinical leads 32

to vasoconstriction of skin as the first tissue bed to react to inadequate oxygen delivery.26 Decreases in PtcO2 are even seen to precede cardiac arrest.5 Others later discovered that the transcutaneous pO2 correlated with oxygen delivery rather than PaO2 when patients were in low flow states.11,27,28 The monitor is very sensitive to changes in perfusion4,12 and has been suggested to be followed as a goal for the end point of resuscitation.9 Identifying numerical values to follow have been difficult in adults as the variability in skin produces a wide range in “normal” values.5,29,30 Therefore, it has been recommended for use as a trend monitor individualized to the patient.13 This concept has led to using the transcutaneous monitor to justify levels of amputations and monitor postoperative tissue flaps.31–33 Tatevossian attempted the translation of PtcO2 values to cardiac hemodynamics when he explored the dependence of PtcO2 on FIO2 using a PtcO2/FIO2 ratio to interpret the trend.34,35 The PtcO2 or FIO2 value correlated with outcome but the values had a wide SD leading to problems in using “one number” as a goal of resuscitation. This led to the Oxygen Challenge test initially described by Jonsson, later Esbroek, and then Waxman using intramuscular pO2.9,14,15 Based on their work, the current Oxygen Challenge test using a noninvasive transcutaneous monitor was developed.3 Recognizing the descriptive nature of this pilot study, it is difficult to discern unequivocally, based on the number of patients studied, if the oxygen challenge test did select the gravest of the group. If these data are verified in larger, prospective studies, the oxygen challenge test may prove to be a simple, noninvasive modality that may serve to objectively refine the stratification of patients with overt or occult shock who may benefit from APC therapy.

CONCLUSION The transcutaneous monitor is a simple, noninvasive way to help to demonstrate tissue perfusion. This tool is readily available in most hospitals with neonatal wards and is relatively inexpensive. The onus on physicians is to identify hypoperfusion early with prompt treatment and reversal of occult shock. The diagnosis of shock is not often established by clinical examination alone. This has implications especially when the formulating a treatment algorithm to use a relatively expensive product that has bleeding side effects. The transcutaneous monitor is a valuable addition to our armentarium. Having an objective measurement to further select patients who may benefit from APC rather than a scoring system may encourage other healthcare practitioners to utilize this drug when needed.

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