To the Editor: The review by Russell (Oct. 19 issue)1 recommendsthe protocol used by Rivers et al.2 and adopted in the SurvivingSepsis Campaign guidelines3 for the initial resuscitation insevere sepsis. Although others4 have warned against the useof this protocol, this warning did not receive the attentionwe think it deserves. Estimates of intravascular volume basedon any given level of filling pressure do not reliably predictthe response to fluid administration. In addition, patientswith sepsis have characteristically high central venous oxygensaturation because of decreased oxygen extraction. The initialmean central venous oxygen saturation of 50% in the study byRivers et al. and the high mortality rate raise the possibilitythat these patients arrived at the hospital in a state of late,untreated, hypovolemic sepsis.5,6 This may be due in part toreduced access to health care and in part to the cost of care.5We believe that the hemodynamic component of these guidelinescannot, at this time, be applied to all patients with sepsis,particularly those in whom sepsis develops while they are inthe hospital. Both physiologically and clinically this protocolmay be wrong for many patients with sepsis.
Azriel Perel, M.D. Eran Segal, M.D. Sheba Medical Center Tel Aviv 52621, Israel perelao{at}shani.net
Dr. Perel reports serving on the advisory board of Pulsion MedicalSystems, Germany.
References
Russell JA. Management of sepsis. N Engl J Med 2006;355:1699-1713. [Erratum, N Engl J Med 2006;355:2267.] [Free Full Text]
Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 2001;345:1368-1377. [Free Full Text]
Dellinger RP, Carlet JM, Masur H, et al. Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock. Crit Care Med 2004;32:858-873. [Erratum, Crit Care Med 2004;32:1448, 2169-70.] [CrossRef][ISI][Medline]
Marik PE, Varon J. Goal-directed therapy for severe sepsis. N Engl J Med 2002;346:1025-1025. [CrossRef][ISI][Medline]
Ho BCH, Bellomo R, McGain F, et al. The incidence and outcome of septic shock patients in the absence of early-goal directed therapy. Crit Care 2006;10:R80-R80. [CrossRef][Medline]
Shapiro NI, Howell MD, Talmor D, et al. Implementation and outcomes of the Multiple Urgent Sepsis Therapies (MUST) protocol. Crit Care Med 2006;34:1025-1032. [CrossRef][ISI][Medline]
To the Editor: Two points in the article by Russell warrantfurther discussion. First, in the discussion of early, goal-directedtherapy, the author recommends maintaining a central venouspressure of 8 to 12 mm Hg. Surviving Sepsis Campaign guidelinesrecommend the same central venous pressure but add that in mechanicallyventilated patients a higher target central venous pressure,12 to 15 mm Hg, is recommended to account for the increasedintrathoracic pressure.1 Second, in the discussion about activatedprotein C, there is one important observation that Russell doesnot mention. In the Administration of Drotrecogin Alfa (Activated)in Early Stage Severe Sepsis (ADDRESS) trial,2 post hoc analysisof the subgroup of patients who had undergone recent surgery(within the previous 30 days) indicated that surgical patientswith single-organ dysfunction who received activated proteinC had a higher 28-day mortality than the placebo group (20.7%vs. 14.1%, P=0.03). This particular finding triggered a retrospectiveanalysis of the same subgroup in the Recombinant Human ActivatedProtein C Worldwide Evaluation in Severe Sepsis (PROWESS) study,and a similar effect was noted.3 This outcome clearly arguesagainst the use of activated protein C in this subgroup of patients.
Aman Khurana, M.D. Namita Vinayek, M.D. Sioux Valley Hospital University of South Dakota Medical Center Sioux Falls, SD 57117 akhurana{at}usd.edu
References
Dellinger RP, Carlet JM, Masur H, et al. Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock. Crit Care Med 2004;32:858-873. [Erratum, Crit Care Med 2004;32:1448, 2169-70.] [CrossRef][ISI][Medline]
Abraham E, Laterre P-F, Garg R, et al. Drotrecogin alfa (activated) for adults with severe sepsis and a low risk of death. N Engl J Med 2005;353:1332-1341. [Free Full Text]
Bernard GR, Vincent JL, Laterre PF, et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001;344:699-709. [Free Full Text]
To the Editor: I wish that Russell's review had included a morecomprehensive discussion of the role of recombinant human activatedprotein C. His coverage of the ADDRESS trial results excludesthe disturbing data on the subgroups of patients with multiple-organfailure and those with an Acute Physiology and Chronic HealthEvaluation (APACHE II) score greater than 24 (approved uses):no treatment benefit was shown, and the 28-day mortality ratewas even higher with activated protein C than with placebo.1,2,3In contrast, favorable data on high-risk subgroups in the PROWESStrial are highlighted. The high overall rate of serious bleedingreported in the Extended Evaluation of Recombinant Human ActivatedProtein C (ENHANCE) trial also deserved comment, in my estimation.1
Russell suggests that activated protein C may be useful in theemergency care of patients with sepsis, yet doubts regardingany role for activated protein C have been expressed. Additionalconcerns have arisen from the PROWESS trial: important differencesbetween study groups in the severity of disease at baseline,especially in higher-risk subgroups2,3; inadequate blinding;differences in the rates of do-not-resuscitate orders; the lackof reduced mortality rates at 28 days among patients withoutsevere, long-term illness; disappointing data on dischargingpatients to home4; and the distinct possibility that meetingthe criteria for stopping the trial early occurred by chance.3
Alasdair F. Mackenzie, F.R.C.A. Queen Margaret Hospital Dunfermline KY12 0SU, United Kingdom alasdair.mackenzie{at}faht.scot.nhs.uk
Anton K.M. Bartelink, M.D. Meander Medisch Centrum 3818 ES Amersfoort, the Netherlands
References
Eichacker PQ, Danner RL, Suffredini AF, Cui X, Natanson C. Reassessing recombinant human activated protein C for sepsis: time for a new randomized controlled trial. Crit Care Med 2005;33:2426-2428. [CrossRef][ISI][Medline]
Carlet J. Prescribing indications based on successful clinical trials in sepsis: a difficult exercise. Crit Care Med 2006;34:525-529. [CrossRef][ISI][Medline]
Gardlund B. Activated protein C (Xigris) treatment in sepsis: a drug in trouble. Acta Anaesthesiol Scand 2006;50:907-910. [CrossRef][ISI][Medline]
Mackenzie AF. Activated protein C: do more survive? Intensive Care Med 2005;31:1624-1626. [CrossRef][ISI][Medline]
To the Editor: The review by Russell states that our randomized,controlled trials investigating the effect of intensive versusconventional insulin therapy in patients in the surgical intensivecare unit (ICU) (1548 patients) and the medical ICU (1200 patients)did not include patients with sepsis.1,2 However, among themixed medical and surgical populations in these randomized,controlled trials, 950 patients could be identified as havingsepsis at the time of admission to the ICU.3,4 We report herethe effect of intensive insulin therapy in the patients withsepsis as compared with the effect in 1798 other patients (Table 1).
Table 1. Characteristics of Patients in the Medical and Surgical Intensive Care Units (ICUs).
Despite a higher incidence of hypoglycemia among patients withsepsis than among those without sepsis (intensive insulin therapy,20% vs. 7%; P<0.001; conventional insulin therapy, 3% vs.1%; P=0.02), the effect of intensive insulin therapy on theoutcome for patients with sepsis was similar to the effect onthe outcome for other patients. This post hoc analysis lackedthe statistical power to prove that the observed 4% absolutereduction in mortality was significant in an intention-to-treatanalysis (this would require 2200 patients per group). However,the 8% absolute reduction in mortality and the 21% reductionin critical illness polyneuropathy among patients with sepsisand long stays in the ICU who were treated with intensive insulintherapy were significant, and the analysis did not reveal harmto patients treated with intensive insulin therapy for lessthan 3 days.
Sophie Van Cromphaut, M.D., Ph.D. Alexander Wilmer, M.D., Ph.D. Greet Van den Berghe, M.D., Ph.D. Catholic University of Leuven B-3000 Leuven, Belgium
References
Van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in critically ill patients. N Engl J Med 2001;345:1359-1367. [Free Full Text]
Van den Berghe G, Wilmer A, Hermans G, et al. Intensive insulin therapy in the medical ICU. N Engl J Med 2006;354:449-461. [Free Full Text]
Van den Berghe G, Wilmer A, Milants I, et al. Intensive insulin therapy in mixed medical/surgical intensive care units: benefit versus harm. Diabetes 2006;55:3151-3159. [Free Full Text]
Bone RC, Balk RA, Cerra FB, et al. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Chest 1992;101:1644-1655. [CrossRef][ISI][Medline]
The author replies: Perel and Segal suggest that filling pressuresdo not reliably predict the response to fluid. Central venousoxygen saturation was very low in the study by Rivers et al.1;thus, they studied late, untreated hypovolemic sepsis. Relationshipsamong central venous oxygen saturation, intravascular volume,fluid therapy, and outcomes are complex. The study by Riverset al. is the only adequately powered trial of early, goal-directedtherapy; unfortunately, there are no similar trials regardinginpatients with sepsis. Although other investigators have foundhigher initial central venous oxygen saturation in patientswith sepsis in the emergency setting2 than did Rivers et al.,additional studies are needed to describe the range of baselinevalues for central venous oxygen saturation in such patients.
Khurana and Vinayek suggest that ventilated patients requirehigher central venous pressure because of increased intrathoracicpressure; I agree. The study by Rivers et al.1 suggests thatthe response of the central venous pressure (and central venousoxygen saturation) to fluid challenge may be helpful in assessingfluid resuscitation. I agree that surgical patients who havesingle-organ dysfunction are at increased risk for death whenthey are treated with activated protein C and therefore shouldnot receive this treatment.
Mackenzie and Bartelink note that there was "no treatment benefit. . . and the 28-day mortality rate was even higherwith activated protein C than with placebo" in a subgroup ofhigh-risk patients in the ADDRESS study.3 The APACHE II high-risksubgroup of the ADDRESS trial was small (324 patients), andthe power was only 0.63 (to refute the mortality results inthe PROWESS trial in high-risk patients absolutely); thus, itis difficult to determine statistically whether the subgroupresult in the ADDRESS trial is a true negative result. The bleedingrates in the ENHANCE trial are difficult to assess because therewas no concurrent control group; however, I would reemphasizethe need for careful assessment and monitoring of patients treatedwith activated protein C. Mackenzie and Bartelink raise concernsregarding the PROWESS trial (my responses are in parentheses),such as baseline characteristics (overall, they were balanced;also see Ely et al.4), inadequate blinding (difficult to assesswithout data about outcomes), do-not-resuscitate rates (difficultto compare with other studies, since do-not-resuscitate ordersare underreported), chronic illness (post hoc subgroup analysiswith inadequate power), disappointing rates of discharge tohome (overall discharge rate was significantly higher [P=0.03]5with activated protein C, especially in the high-risk APACHEII subgroup), and early stopping by chance (the overall P valueof 0.005 suggests a 5 in 1000 chance of a false positive result).
I thank Van Cromphaut and colleagues for reporting on subgroupsof patients with sepsis from their trials of intensive insulintherapy.6,7 They argue that intensive insulin therapy decreasedmortality among patients with sepsis who had a long stay inthe ICU (3 days). This post hoc subgroup analysis is hypothesisgenerating and indicates the need for a trial that examinesthe association between the duration of the ICU stay and intensiveinsulin therapy in patients with sepsis.
Before the publication of my article, I informed the Journalthat I had received grant support from Eli Lilly, Chiron, andGlaxo. This information was inadvertently omitted from the article.
James A. Russell, M.D. University of British Columbia Vancouver, BC V6Z 1Y6, Canada jrussell{at}mrl.ubc.ca
References
Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 2001;345:1368-1377. [Free Full Text]
Shapiro NI, Howell MD, Talmor D, et al. Implementation and outcomes of the Multiple Urgent Sepsis Therapies (MUST) protocol. Crit Care Med 2006;34:1025-1032. [CrossRef][ISI][Medline]
Abraham E, Laterre P-F, Garg R, et al. Drotrecogin alfa (activated) for adults with severe sepsis and a low risk of death. N Engl J Med 2005;353:1332-1341. [Free Full Text]
Ely EW, Laterre PF, Angus DC, Bernard GK. Drotrecogin alfa (activated) administration: too many subgroups. Crit Care Med 2003;10:2564-2565.
Angus DC, Laterre PF, Helterbrand J, et al. The effect of drotrecogin alfa (activated) on long-term survival after severe sepsis. Crit Care Med 2004;32:2199-2206. [ISI][Medline]
Van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in critically ill patients. N Engl J Med 2001;345:1359-1367. [Free Full Text]
Van den Berghe G, Wilmer A, Hermans G, et al. Intensive insulin therapy in the medical ICU. N Engl J Med 2006;354:449-461. [Free Full Text]
Correction
to
Russell, 
3 days). This post hoc subgroup analysis is hypothesis generating and indicates the need for a trial that examines the association between the duration of the ICU stay and intensive insulin therapy in patients with sepsis. 
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