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Does adoption of a regional sepsis protocol reduce mortality? , ☆☆ In November 2008, Northern California Kaiser Permanente (KP), which is the largest health maintenance organization in the United States, adopted a regional sepsis protocol [1] based on a study published by Rivers et al [2] in 2001 in which it was reported that early goal-directed therapy(EGDT) led to a 16% absolute reduction in sepsis mortality. Subsequent to adoption of the EGDT protocol, KP representatives have published claims of even greater reductions in sepsis mortality than originally reported in the study of Rivers et al [1,3-6]. The object of this correspondence is to analyze whether the available KP data support these claims. Kaiser Permanente representatives have based their claims of improved sepsis care on declining rates of sepsis mortality calculated as the percentage of patients admitted with a sepsis-related diagnosis who died [1,3-6]. This rate varies inversely with sepsis admission volume and is referred to, subsequently, in this correspondence as sepsis admission volume-dependent (SAV-D) mortality. The rate of patients dying of sepsis per 1000 admissions for all causes is less dependent on sepsis admission rates because sepsis admissions account for a small fraction of total hospital admissions and is referred to, subsequently, as sepsis admission volume-independent (SAV-I) mortality. Kaiser Permanente representatives have not directly reported SAV-I mortality, but raw data included with a KP regional newsletter [3] allow one to calculate this rate. These raw data include the total monthly sepsis admission and sepsis mortality volumes during a 50- month period, from January 2006 through February 2010. The data also include the mean rates of sepsis-related admissions per 1000 admissions for all causes for 3 epochs; epoch 1, from January 2006 to November 2008, the date of adoption of the EGDT protocol; epoch 2, from November 2008 through June 2009 immediately after adoption of the EGDT protocol; and epoch 3, from July 2009 through February 2010, during which adherence to the EGDT protocol was actively promoted throughout the 21 Northern California KP medical centers. Using the available raw KP data, the author calculated the total number of admissions for all causes for each of the 3 epochs by dividing the reported sepsis admission volumes by the reported mean sepsis admission rates. The author calculated SAV-D sepsis mortality by dividing sepsis mortality volume by sepsis admission volume, and SAV-I sepsis mortality by dividing sepsis mortality volume by total admission volume. The author calculated condence intervals using the Normal Approximation Method with Microsoft Excel 2010 software (Redmond, WA). As shown in Table and Fig., SAV-D sepsis mortality declined from 24.2% in epoch 1 to 15.7% in epoch 3, but over the same period, the sepsis admission rate rose even more sharply, and there was a small but statistically signicant increase in SAV-I sepsis mortality, from 8.6 in epoch 1 to 10.3 in epoch 3. If one accepts KP's claims that adoption of the regional sepsis protocol led to improved care, then to reconcile these claims with the KP data and mortality rates shown in Table and Fig., one must postulate that either a sepsis outbreak coincidentally struck Northern California just at the same time that KP adopted the EGDT protocol, or that prior to adoption of the protocol, not only were KP physicians failing to correctly diagnose a signicant number of septic patients when they rst saw them, they were also failing to recognize that the patients were septic when they died. A much more likely explanation for KP data is that there was no net improvement in sepsis care after adoption of the EGDT protocol, but that after adoption of the protocol, KP physicians began applying less stringent criteria for making the diagnosis of sepsis. As part of implementation of the protocol, KP physicians were encouraged to dene sepsis as Suspected infection and the presence of two or more signs of the systemic inammatory response syndrome (SIRS)[1]. It has been noted that SIRS criteria include relatively minor perturbations in vital signs and white blood count and that dening sepsis based on SIRS criteria is a marked departure from sepsis as we have known it.the Table Sepsis admission and mortality volume and rates Epoch 1 Epoch 2 Epoch 3 Sepsis admission volume 16 049 4584 6791 Sepsis mortality volume 3883 937 1064 Total admission volume 450 182 107 178 103 569 Sepsis admission rate (95% condence intervals) 35.7 (35.1-36.2) 42.8 (41.6-44.0) 65.6 (64.1-67.1) SAV-D sepsis mortality (95% condence intervals) 24.2% (23.5-24.9) 20.4% (19.3-21.6) 15.7% (14.8-16.5) SAV-I sepsis mortality (95% condence intervals) 8.6 (8.4-8.9) 8.7 (8.2-9.3) 10.3 (9.7-10.9) Epoch 1, January 2006 to November 2008, the 34-month period prior to adoption of EGDT protocol. Epoch 2, November, 2008 through June, 2009, the 8-month period immediately after adoption of the EGDT protocol. Epoch 3, July 2009 through February 2010, the 8-month period during active promotion of adherence to EGDT protocol. Sepsis admission volume, total number of patients admitted with a sepsis-related diagnosis; sepsis mortality volume, total number of patients dying of sepsis; total admission volume, total number of hospital admissions for all causes; sepsis admission rate, number of patients admitted with sepsis-related diagnosis per 1,000 admissions for all causes; SAV-D, percentage of patients admitted with a sepsis-related diagnosis who died of sepsis; SAV-I, number of patients who died of sepsis per 1000 admissions for all causes. Fig. Sepsis admission and mortality rates. Vertical bars indicate 95% condence intervals. Epoch 1, January 2006 to November 2008, the 34-month period prior to adoption of EGDT protocol. Epoch 2, November, 2008 through June, 2009, the 8-month period immediately after adoption of the EGDT protocol. Epoch 3, July 2009 through February 2010, the 8-month period during active promotion of adherence to EGDT protocol. Sepsis admission rate, number of patients admitted with sepsis-related diagnosis per 1000 admissions for all causes; SAV-D, percentage of patients admitted with a sepsis-related diagnosis who died of sepsis; SAV-I, number of patients who died of sepsis per 1000 admissions for all causes. References [1] Kaul V, Imam SH, Gambhir HS, Sangha A, Nandavaram S. Am J Emerg Med 2013;31(10):1536.e34. [2] Brubacher, Jeffrey R. Salicylism from topical salicylates: review of the literature. Read more: http://informahealthcare.com/doi/abs/10.3109/15563659609013814? journalCode=ctx. Clinical Toxicology. 34.4 (1996):431436. Print. Source(s) of funding: None. ☆☆ Name of organization and date of assembly if the article has been presented: Not applicable. 280 Correspondence / American Journal of Emergency Medicine 32 (2014) 277285

Does adoption of a regional sepsis protocol reduce mortality?

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Does adoption of a regional sepsis protocolreduce mortality?☆,☆☆

In November 2008, Northern California Kaiser Permanente (KP),which is the largest health maintenance organization in the UnitedStates, adopted a regional sepsis protocol [1] based on a studypublished by Rivers et al [2] in 2001 in which it was reported that“early goal-directed therapy” (EGDT) led to a 16% absolute reductionin sepsis mortality. Subsequent to adoption of the EGDT protocol, KPrepresentatives have published claims of even greater reductions insepsis mortality than originally reported in the study of Rivers et al[1,3-6]. The object of this correspondence is to analyze whether theavailable KP data support these claims.

Kaiser Permanente representatives have based their claims ofimproved sepsis care on declining rates of sepsis mortality calculatedas the percentage of patients admitted with a sepsis-related diagnosiswho died [1,3-6]. This rate varies inversely with sepsis admissionvolumeand is referred to, subsequently, in this correspondenceas sepsisadmission volume-dependent (SAV-D) mortality. The rate of patientsdying of sepsis per 1000 admissions for all causes is less dependent onsepsis admission rates because sepsis admissions account for a smallfraction of total hospital admissions and is referred to, subsequently, assepsis admission volume-independent (SAV-I) mortality.

Kaiser Permanente representatives have not directly reportedSAV-I mortality, but raw data included with a KP regional newsletter[3] allow one to calculate this rate. These raw data include the totalmonthly sepsis admission and sepsis mortality volumes during a 50-month period, from January 2006 through February 2010. The dataalso include the mean rates of sepsis-related admissions per 1000admissions for all causes for 3 epochs; epoch 1, from January 2006 toNovember 2008, the date of adoption of the EGDT protocol; epoch 2,from November 2008 through June 2009 immediately after adoptionof the EGDT protocol; and epoch 3, from July 2009 through February2010, during which adherence to the EGDT protocol was activelypromoted throughout the 21 Northern California KP medical centers.

Using the available raw KP data, the author calculated the totalnumber of admissions for all causes for each of the 3 epochs bydividing the reported sepsis admission volumes by the reported meansepsis admission rates. The author calculated SAV-D sepsis mortalityby dividing sepsis mortality volume by sepsis admission volume, andSAV-I sepsis mortality by dividing sepsis mortality volume by totaladmission volume. The author calculated confidence intervals usingthe Normal Approximation Method with Microsoft Excel 2010software (Redmond, WA).

As shown in Table and Fig., SAV-D sepsis mortality declined from24.2% in epoch 1 to 15.7% in epoch 3, but over the same period, thesepsis admission rate rose even more sharply, and there was a smallbut statistically significant increase in SAV-I sepsis mortality, from 8.6in epoch 1 to 10.3 in epoch 3.

If one accepts KP's claims that adoption of the regional sepsisprotocol led to improved care, then to reconcile these claimswith the KPdata andmortality rates shown inTable and Fig., onemustpostulate that

either a sepsis outbreak coincidentally struck Northern California just atthe same time that KP adopted the EGDT protocol, or that prior toadoption of the protocol, not onlywere KPphysicians failing to correctlydiagnose a significant number of septic patients when they first sawthem, they were also failing to recognize that the patients were septicwhen they died. Amuchmore likely explanation for KPdata is that therewas no net improvement in sepsis care after adoption of the EGDTprotocol, but that after adoption of the protocol, KP physicians beganapplying less stringent criteria formaking the diagnosis of sepsis. As partof implementation of the protocol, KP physicians were encouraged todefine sepsis as “Suspected infection and the presence of two or moresignsof the systemic inflammatory response syndrome(SIRS)” [1]. It hasbeen noted that SIRS criteria include relatively minor perturbations invital signs andwhite blood count and that defining sepsis based on SIRScriteria is a marked departure from “sepsis as we have known it….the

TableSepsis admission and mortality volume and rates

Epoch 1 Epoch 2 Epoch 3

Sepsis admissionvolume

16 049 4584 6791

Sepsis mortalityvolume

3883 937 1064

Total admissionvolume

450 182 107 178 103 569

Sepsis admission rate(95% confidenceintervals)

35.7 (35.1-36.2) 42.8 (41.6-44.0) 65.6 (64.1-67.1)

SAV-D sepsis mortality(95% confidenceintervals)

24.2% (23.5-24.9) 20.4% (19.3-21.6) 15.7% (14.8-16.5)

SAV-I sepsis mortality(95% confidenceintervals)

8.6 (8.4-8.9) 8.7 (8.2-9.3) 10.3 (9.7-10.9)

Epoch 1, January 2006 to November 2008, the 34-month period prior to adoption ofEGDT protocol. Epoch 2, November, 2008 through June, 2009, the 8-month periodimmediately after adoption of the EGDT protocol. Epoch 3, July 2009 through February2010, the 8-month period during active promotion of adherence to EGDT protocol.Sepsis admission volume, total number of patients admitted with a sepsis-relateddiagnosis; sepsis mortality volume, total number of patients dying of sepsis; totaladmission volume, total number of hospital admissions for all causes; sepsis admissionrate, number of patients admitted with sepsis-related diagnosis per 1,000 admissionsfor all causes; SAV-D, percentage of patients admitted with a sepsis-related diagnosiswho died of sepsis; SAV-I, number of patients who died of sepsis per 1000 admissionsfor all causes.

Fig. Sepsis admission and mortality rates. Vertical bars indicate 95% confidenceintervals. Epoch 1, January 2006 to November 2008, the 34-month period prior toadoption of EGDT protocol. Epoch 2, November, 2008 through June, 2009, the 8-monthperiod immediately after adoption of the EGDT protocol. Epoch 3, July 2009 throughFebruary 2010, the 8-month period during active promotion of adherence to EGDTprotocol. Sepsis admission rate, number of patients admitted with sepsis-relateddiagnosis per 1000 admissions for all causes; SAV-D, percentage of patients admittedwith a sepsis-related diagnosis who died of sepsis; SAV-I, number of patients who diedof sepsis per 1000 admissions for all causes.

References

[1] Kaul V, Imam SH, Gambhir HS, Sangha A, Nandavaram S. Am J Emerg Med2013;31(10):1536.e3–4.

[2] Brubacher, Jeffrey R. Salicylism from topical salicylates: review of the literature.Read more: http://informahealthcare.com/doi/abs/10.3109/15563659609013814?journalCode=ctx. Clinical Toxicology. 34.4 (1996):431–436. Print.

☆ Source(s) of funding: None.☆☆ Name of organization and date of assembly if the article has been presented:

Not applicable.

280 Correspondence / American Journal of Emergency Medicine 32 (2014) 277–285

condition of a very sick infectedpatient” [7]. Thepresenceof SIRS criteriadoes not predict in-hospital or 1-year mortality in patients admittedwith suspected sepsis [8].

Numerous concerns have been raised previously about the study ofRivers et al [2], upon which the KP regional sepsis protocol is based,including concerns about potential harmful effects of individualelements of the EGDT protocol [9-12] and the validity of the study asawhole [13-16]. The small but statistically significant increase in SAV-Isepsis mortality seen in the Northern California KP region afteradoption of the EGDT protocol suggests that actively encouragingphysicians to adhere to this protocol may have a net deleterious effecton sepsis care that more than outweighs any increase in sepsisawareness that would be expected to accompany such a campaign.

William Durston, MDDepartment of Emergency Medicine

Kaiser Foundation HospitalSacramento, CA

E-mail addresses: [email protected]@kp.org

http://dx.doi.org/10.1016/j.ajem.2013.11.035

References

[1] Whippy A, Skeath M, Crawford B, et al. Kaiser Permanente's performanceimprovement system, part 3: multisite improvements in care for patients withsepsis. Jt Comm J Qual Patient Saf 2011;37:483–93.

[2] Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in the treatment ofsevere sepsis and septic shock. N Engl J Med 2001;345:1368–77.

[3] SepsisControlChartsFebruary2010,attachmenttoAdamsC,PoropatL.KaiserPermanenteNorthern California Sepsis Collaborative Newsletter. Vol. 2 Issue 3, March 15, 2010.

[4] Crawford B, Skeath M, Whippy A. Kaiser Northern California sepsis mortalityreduction initiative. Crit Care 2012;16(Suppl 3):12.

[5] Whippy A, Skeath M. Multihospital system uses pro-active screening, algorithms,and tools to improve sepsis care, leading to more appropriate care and betteroutcomes. U.S. Department of Health and Human Services Agency for HealthcareResearch and Quality website. http://www.innovations.ahrq.gov/content.aspx?id=3660. Accessed September 10, 2013.

[6] Pearl R. Why 70,000 Americans die needlessly in hospitals every year.Forbes online. August 8, 2013. http://www.forbes.com/sites/robertpearl/2013/08/08/why-70000-americans-die-needlessly-in-hospitals-each-year/2/.Accessed September 10, 2013.

[7] Talan D. Dear SIRS: it's time to return to sepsis as we have known it. Ann EmergMed 2006;48:591–2.

[8] Shapiro N, Howell MD, Bates DW, et al. The association of sepsis syndrome andorgan dysfunction with mortality in emergency department patients withsuspected infection. Ann Emerg Med 2006;48:583–90.

[9] Marik PE, Varon J. Goal directed therapy for severe sepsis (letter). N Engl J Med2002;346:1025.

[10] Boyd J, Forbes J, Nakada T, et al. Fluid resuscitation in septic shock: a positive fluidbalance and elevated central venous pressure are associated with increasedmortality. Crit Care Med 2011;39:259–65.

[11] Marik PE, Corwin HL. Efficacy of RBC transfusion in the critically ill: a systematicreview of the literature. Crit Care Med 2008;36:2667–74.

[12] Hayes MA, Timmins AC, Yau EH, et al. Elevation of systemic oxygen delivery in thetreatment of critically ill patients. N Engl J Med 1994;330:1717–22.

[13] Abroug F, Besbes L, Nouira S. Goal-directed therapy for severe sepsis (letter).N Engl J Med 2002;346:1025.

[14] Sarkar S, Kupfer Y, Tessler S. Goal-directed therapy for severe sepsis (letter).N Engl J Med 2002;346:1026.

[15] Burton TM. New therapy for sepsis infections raises hope but manyquestions. Wall Street Journal, August 14, 2008, p. A1. http://online.wsj.com/article/SB121867179036438865.html. Accessed September 13, 2013.

[16] Marik P, Varon J. Early goal-directed therapy: on terminal life support? Am JEmerg Med 2010;28:243–5.

The author’s reply

We are grateful to the thoughtful authors who took time and greateffort to ponder the use of sidestream darkfield imaging in theevaluation of acutely decompensated heart failure (HF) in theemergency department setting. Our work evaluating perfused

capillary density (PCD) represented an initial attempt at definingthis population [1], which is infamously variable.

Our colleagues raise salient points that reflect the challenges westruggled with in study design and implementation, such as enrollingsubjects prior to treatment (rendered by pre-arrival EMS), the widevariation in treatment types, and the variation in the treatmentresponse. After 2 years of enrollment, we finally met our sample size,and despite other intriguing questions that we really wanted toanswer, it was time to present this data.

The good news is that data acquisition and interpretation is gettingeasier. Images can be recorded digitally and stored, and the softwareenables easier and timely PCD calculation. Current work is underwayto develop programs thatwill generate a PCD value inminutes,makingbedside decision making a possibility. If our work has added onecontribution to this body of literature, it is that measurement of PCDcan be done reliably among individuals, based on our κ score of 0.95.While the other parameters the author references, explored bydeBacker and later by deUil [2], add more texture to assessment ofthe microvascular perfusion status, we struggle with how toincorporate these time-consuming calculations into a bedside assess-ment tool that can make timely treatment decisions. The inter-ratervariability of these added assessors also needs to be determined.

The bad news is that HF is still a horrendous disease to assess andtreat, regardless of the clinical setting. So our colleagues are quitecorrect that a single PCD cannot stand alone as an assessor of HFseverity, response to treatment or as a prognosticator. We advocate,and are shortly presenting data to address this point, that theresponse and trends to treatment may be the key to managing HFwith microvascular assessment.

I suspect our wide degrees of variation in the absolute number aswell as the change inPCDwasbecauseweenrolledpatientswithvaryingstages and degrees of HF. We contend that a patient with early HF, whohas not developed the endothelial dysfunction in the microvasculaturethat may occur in those with more advanced disease, will be a betterresponder to nitroglycerin. The parameters encountered may differsignificantly when compared to patientswithmore severe disease, suchas those studied in theworkof denUil [2]. Added to this complexity is thepossibility that microvascular perfusion parameters and changes withtreatment may differ in patients on chronic nitrates who may havedown-regulated nitric oxide synthase. Unfortunately, this manuscriptcould not further explore these intricacies. Our patients who had poorperfusion parameters and later died in our study most likely had moreadvanced disease, and we will need larger numbers of patients todetermine the nuances of PCD and its changes with treatment.

The use of medications currently utilized in the HF population,such as nitroglycerin and furosemide, is our next step in this research,guiding these treatments based on microvascular perfusion. It isinteresting that furosemide had any impact on microvascularperfusion, as the 2007 American College of Emergency PhysiciansGuideline specifically state standalone diuresis has not clinically beenshown to be of benefit [3].

So, is PCD ready for clinical bedsidemanagement? No, but we hopeto get there by assessing serial measurement and by incorporatingother assessors of the microvasculature that have shown promise,such as tissue oxygenation [4]. If my colleague is curious regarding therepeated microvascular measurements as treatment is given to thesepatients as they are admitted and beyond, I would suggest not lettinghis subscription to the American Journal of Emergency Medicine lapse.

Sincerely,

Sébastien Champion, MDRéanimation médicale et toxicologique, Lariboisière Hospital

2 rue A. Paré, 75010 Paris, FranceE-mail address: [email protected]

http://dx.doi.org/10.1016/j.ajem.2013.11.041

281Correspondence / American Journal of Emergency Medicine 32 (2014) 277–285