Limits...
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.

Show MeSH

Related in: MedlinePlus

Mean protein C activity levels over time for PROWESS placebo patients classified according to timing of death [34]. Shown are means and standard errors (SE) of protein C levels based on time of death of PROWESS [9] drotrecogin alfa (activated) patients. Raw values with no imputation are included. PROWESS, Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2230608&req=5

Figure 1: Mean protein C activity levels over time for PROWESS placebo patients classified according to timing of death [34]. Shown are means and standard errors (SE) of protein C levels based on time of death of PROWESS [9] drotrecogin alfa (activated) patients. Raw values with no imputation are included. PROWESS, Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis.

Mentions: Even though severe protein C deficiency at baseline clearly indicates a much greater risk for death, it is of note that there is an additional approximate 20% mortality between days 4 and 28 in all three groups, independent of baseline protein C levels. Based on this observation, additional analyses were performed to investigate whether sequential measurements of protein C levels would add further prognostic value. In PROWESS, protein C levels were measured daily on study days 1 to 7, 14 and 28. Figure 1 shows sequential protein C measurements in PROWESS placebo patients grouped by duration of survival [34]. In addition to the observation noted above that very low protein C levels predict early death, it was also demonstrated that survival beyond day 28 or hospital discharge was associated with an early return of endogenous protein C to above the lower limit of normal. Inability to increase endogenous protein C level to the normal range was indicative of poor outcome.


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 levels over time for PROWESS placebo patients classified according to timing of death [34]. Shown are means and standard errors (SE) of protein C levels based on time of death of PROWESS [9] drotrecogin alfa (activated) patients. Raw values with no imputation are included. 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 1: Mean protein C activity levels over time for PROWESS placebo patients classified according to timing of death [34]. Shown are means and standard errors (SE) of protein C levels based on time of death of PROWESS [9] drotrecogin alfa (activated) patients. Raw values with no imputation are included. PROWESS, Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis.
Mentions: Even though severe protein C deficiency at baseline clearly indicates a much greater risk for death, it is of note that there is an additional approximate 20% mortality between days 4 and 28 in all three groups, independent of baseline protein C levels. Based on this observation, additional analyses were performed to investigate whether sequential measurements of protein C levels would add further prognostic value. In PROWESS, protein C levels were measured daily on study days 1 to 7, 14 and 28. Figure 1 shows sequential protein C measurements in PROWESS placebo patients grouped by duration of survival [34]. In addition to the observation noted above that very low protein C levels predict early death, it was also demonstrated that survival beyond day 28 or hospital discharge was associated with an early return of endogenous protein C to above the lower limit of normal. Inability to increase endogenous protein C level to the normal range was indicative of poor outcome.

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