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The protein C pathway: implications for the design of the RESPOND study.

Vangerow B, Shorr AF, Wyncoll D, Janes J, Nelson DR, Reinhart K - Crit Care (2007)

Bottom Line: The predictive value of plasma protein C level in sepsis has been demonstrated in a number of studies in which depressed protein C levels were associated with increased likelihood of negative outcome.The duration of DrotAA infusion in the alternative therapy arm depends on the individual response in terms of sustained increase in endogenous protein C.The ultimate aims of this and potential following studies are as follows: to establish serial plasma protein C measurement as a biomarker that will aid in the identification of severe sepsis patients who are most likely to benefit from DrotAA therapy, to enable adjustment of DrotAA therapy in individual patients (specifically, the possibility to use a higher dose and to adjust the infusion duration), and to provide guidance to the clinician regarding whether the patient is responding to DrotAA.

View Article: PubMed Central - HTML - PubMed

Affiliation: Eli Lilly Critical Care Europe, Air Center, 1214 Vernier/Geneva, Switzerland. vangerow_burkhard@lilly.com

ABSTRACT
The predictive value of plasma protein C level in sepsis has been demonstrated in a number of studies in which depressed protein C levels were associated with increased likelihood of negative outcome. Data from the PROWESS (Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis) trial indicate that administration of drotrecogin alfa (activated; DrotAA) leads to an increase in endogenous protein C levels in severe sepsis patients. In a group as heterogeneous as sepsis patients, the currently approved dose and duration of administration (24 mug/kg per hour for 96 hours) might not be optimal in some individuals. The RESPOND (Research Evaluating Serial Protein C levels in severe sepsis patients ON Drotrecogin alfa [activated]) trial is a phase II study being conducted to explore the use of endogenous protein C level as both a biomarker and a steering parameter for administration of DrotAA. Eligible patients will receive DrotAA either at the normal, currently approved dose and duration of administration ('standard therapy') or at a higher dose with variable infusion duration or variable infusion duration only ('alternative therapy'). The duration of DrotAA infusion in the alternative therapy arm depends on the individual response in terms of sustained increase in endogenous protein C. The ultimate aims of this and potential following studies are as follows: to establish serial plasma protein C measurement as a biomarker that will aid in the identification of severe sepsis patients who are most likely to benefit from DrotAA therapy, to enable adjustment of DrotAA therapy in individual patients (specifically, the possibility to use a higher dose and to adjust the infusion duration), and to provide guidance to the clinician regarding whether the patient is responding to DrotAA.

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Mean protein C activity over time for selected PROWESS DrotAA patients classified by timing of death. Presented are means and standard errors (SE) of protein C levels based on time of death of PROWESS [9] DrotAA patients. Raw values with no imputation are included. Note that not all groups are shown. DrotAA, drotrecogin alfa (activated); PROWESS, Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis.
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Figure 5: Mean protein C activity over time for selected PROWESS DrotAA patients classified by timing of death. Presented are means and standard errors (SE) of protein C levels based on time of death of PROWESS [9] DrotAA patients. Raw values with no imputation are included. Note that not all groups are shown. DrotAA, drotrecogin alfa (activated); PROWESS, Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis.

Mentions: Although most patients in PROWESS and ENHANCE had higher protein C levels at the end of the infusion, there remained a substantial number of patients who were protein C deficient despite treatment with DrotAA. Figure 5 shows the results of sequential protein C measurements in patients treated with DrotAA. Analysis of protein C levels in patients who died after completing the DrotAA infusion (during study days 6 to 15) revealed that protein C levels gradually increased during the infusion, but mean protein C levels at the end of the infusion were less than three-quarters of the lower limit of normal and decreased after the infusion was completed. These patients may have benefited from a longer duration of infusion. Patients who died during the infusion were severely protein C deficient at baseline and exhibited no increase in protein C level during the infusion. These patients would not have had the opportunity to benefit from a longer infusion duration alone, but they may have benefited from an increased dose of DrotAA together, perhaps, with a longer infusion. Such hypotheses have been incorporated into the RESPOND study design.


The protein C pathway: implications for the design of the RESPOND study.

Vangerow B, Shorr AF, Wyncoll D, Janes J, Nelson DR, Reinhart K - Crit Care (2007)

Mean protein C activity over time for selected PROWESS DrotAA patients classified by timing of death. Presented are means and standard errors (SE) of protein C levels based on time of death of PROWESS [9] DrotAA patients. Raw values with no imputation are included. Note that not all groups are shown. DrotAA, drotrecogin alfa (activated); PROWESS, Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2230608&req=5

Figure 5: Mean protein C activity over time for selected PROWESS DrotAA patients classified by timing of death. Presented are means and standard errors (SE) of protein C levels based on time of death of PROWESS [9] DrotAA patients. Raw values with no imputation are included. Note that not all groups are shown. DrotAA, drotrecogin alfa (activated); PROWESS, Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis.
Mentions: Although most patients in PROWESS and ENHANCE had higher protein C levels at the end of the infusion, there remained a substantial number of patients who were protein C deficient despite treatment with DrotAA. Figure 5 shows the results of sequential protein C measurements in patients treated with DrotAA. Analysis of protein C levels in patients who died after completing the DrotAA infusion (during study days 6 to 15) revealed that protein C levels gradually increased during the infusion, but mean protein C levels at the end of the infusion were less than three-quarters of the lower limit of normal and decreased after the infusion was completed. These patients may have benefited from a longer duration of infusion. Patients who died during the infusion were severely protein C deficient at baseline and exhibited no increase in protein C level during the infusion. These patients would not have had the opportunity to benefit from a longer infusion duration alone, but they may have benefited from an increased dose of DrotAA together, perhaps, with a longer infusion. Such hypotheses have been incorporated into the RESPOND study design.

Bottom Line: The predictive value of plasma protein C level in sepsis has been demonstrated in a number of studies in which depressed protein C levels were associated with increased likelihood of negative outcome.The duration of DrotAA infusion in the alternative therapy arm depends on the individual response in terms of sustained increase in endogenous protein C.The ultimate aims of this and potential following studies are as follows: to establish serial plasma protein C measurement as a biomarker that will aid in the identification of severe sepsis patients who are most likely to benefit from DrotAA therapy, to enable adjustment of DrotAA therapy in individual patients (specifically, the possibility to use a higher dose and to adjust the infusion duration), and to provide guidance to the clinician regarding whether the patient is responding to DrotAA.

View Article: PubMed Central - HTML - PubMed

Affiliation: Eli Lilly Critical Care Europe, Air Center, 1214 Vernier/Geneva, Switzerland. vangerow_burkhard@lilly.com

ABSTRACT
The predictive value of plasma protein C level in sepsis has been demonstrated in a number of studies in which depressed protein C levels were associated with increased likelihood of negative outcome. Data from the PROWESS (Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis) trial indicate that administration of drotrecogin alfa (activated; DrotAA) leads to an increase in endogenous protein C levels in severe sepsis patients. In a group as heterogeneous as sepsis patients, the currently approved dose and duration of administration (24 mug/kg per hour for 96 hours) might not be optimal in some individuals. The RESPOND (Research Evaluating Serial Protein C levels in severe sepsis patients ON Drotrecogin alfa [activated]) trial is a phase II study being conducted to explore the use of endogenous protein C level as both a biomarker and a steering parameter for administration of DrotAA. Eligible patients will receive DrotAA either at the normal, currently approved dose and duration of administration ('standard therapy') or at a higher dose with variable infusion duration or variable infusion duration only ('alternative therapy'). The duration of DrotAA infusion in the alternative therapy arm depends on the individual response in terms of sustained increase in endogenous protein C. The ultimate aims of this and potential following studies are as follows: to establish serial plasma protein C measurement as a biomarker that will aid in the identification of severe sepsis patients who are most likely to benefit from DrotAA therapy, to enable adjustment of DrotAA therapy in individual patients (specifically, the possibility to use a higher dose and to adjust the infusion duration), and to provide guidance to the clinician regarding whether the patient is responding to DrotAA.

Show MeSH
Related in: MedlinePlus