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

References [1] Kaul V, Imam SH, Gambhir HS, Sangha A, Nandavaram S. Am J Emerg Med 2013;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.

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 50month 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 confidence 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 significant 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

☆ Source(s) of funding: None. ☆☆ Name of organization and date of assembly if the article has been presented: Not applicable.

Table Sepsis admission and mortality volume and rates

Sepsis admission volume Sepsis mortality volume Total admission volume Sepsis admission rate (95% confidence intervals) SAV-D sepsis mortality (95% confidence intervals) SAV-I sepsis mortality (95% confidence intervals)

Epoch 1

Epoch 2

Epoch 3

16 049

4584

6791

3883

937

1064

450 182

107 178

103 569

35.7 (35.1-36.2)

42.8 (41.6-44.0)

65.6 (64.1-67.1)

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

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.

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 significant number of septic patients when they first 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 define sepsis as “Suspected infection and the presence of two or more signs of the systemic inflammatory response syndrome (SIRS)” [1]. It has been noted that SIRS criteria include relatively minor perturbations in vital signs and white blood count and that defining sepsis based on SIRS criteria is a marked departure from “sepsis as we have known it….the

Fig. Sepsis admission and mortality rates. Vertical bars indicate 95% confidence 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.

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

condition of a very sick infected patient” [7]. The presence of SIRS criteria does not predict in-hospital or 1-year mortality in patients admitted with suspected sepsis [8]. Numerous concerns have been raised previously about the study of Rivers et al [2], upon which the KP regional sepsis protocol is based, including concerns about potential harmful effects of individual elements of the EGDT protocol [9-12] and the validity of the study as a whole [13-16]. The small but statistically significant increase in SAV-I sepsis mortality seen in the Northern California KP region after adoption of the EGDT protocol suggests that actively encouraging physicians to adhere to this protocol may have a net deleterious effect on sepsis care that more than outweighs any increase in sepsis awareness that would be expected to accompany such a campaign. William Durston, MD Department of Emergency Medicine Kaiser Foundation Hospital Sacramento, CA E-mail addresses: [email protected] [email protected] http://dx.doi.org/10.1016/j.ajem.2013.11.035 References [1] Whippy A, Skeath M, Crawford B, et al. Kaiser Permanente's performance improvement system, part 3: multisite improvements in care for patients with sepsis. 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 of severe sepsis and septic shock. N Engl J Med 2001;345:1368–77. [3] Sepsis Control Charts February 2010, attachment to Adams C, Poropat L. Kaiser Permanente Northern California Sepsis Collaborative Newsletter. Vol. 2 Issue 3, March 15, 2010. [4] Crawford B, Skeath M, Whippy A. Kaiser Northern California sepsis mortality reduction 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 better outcomes. U.S. Department of Health and Human Services Agency for Healthcare Research 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 Emerg Med 2006;48:591–2. [8] Shapiro N, Howell MD, Bates DW, et al. The association of sepsis syndrome and organ dysfunction with mortality in emergency department patients with suspected infection. Ann Emerg Med 2006;48:583–90. [9] Marik PE, Varon J. Goal directed therapy for severe sepsis (letter). N Engl J Med 2002;346:1025. [10] Boyd J, Forbes J, Nakada T, et al. Fluid resuscitation in septic shock: a positive fluid balance and elevated central venous pressure are associated with increased mortality. Crit Care Med 2011;39:259–65. [11] Marik PE, Corwin HL. Efficacy of RBC transfusion in the critically ill: a systematic review 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 the treatment 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 many questions. 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 J Emerg Med 2010;28:243–5.

The author’s reply We are grateful to the thoughtful authors who took time and great effort to ponder the use of sidestream darkfield imaging in the evaluation of acutely decompensated heart failure (HF) in the emergency department setting. Our work evaluating perfused

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capillary density (PCD) represented an initial attempt at defining this population [1], which is infamously variable. Our colleagues raise salient points that reflect the challenges we struggled with in study design and implementation, such as enrolling subjects prior to treatment (rendered by pre-arrival EMS), the wide variation in treatment types, and the variation in the treatment response. After 2 years of enrollment, we finally met our sample size, and despite other intriguing questions that we really wanted to answer, it was time to present this data. The good news is that data acquisition and interpretation is getting easier. Images can be recorded digitally and stored, and the software enables easier and timely PCD calculation. Current work is underway to develop programs that will generate a PCD value in minutes, making bedside decision making a possibility. If our work has added one contribution to this body of literature, it is that measurement of PCD can be done reliably among individuals, based on our κ score of 0.95. While the other parameters the author references, explored by deBacker and later by deUil [2], add more texture to assessment of the microvascular perfusion status, we struggle with how to incorporate these time-consuming calculations into a bedside assessment tool that can make timely treatment decisions. The inter-rater variability of these added assessors also needs to be determined. The bad news is that HF is still a horrendous disease to assess and treat, regardless of the clinical setting. So our colleagues are quite correct that a single PCD cannot stand alone as an assessor of HF severity, response to treatment or as a prognosticator. We advocate, and are shortly presenting data to address this point, that the response and trends to treatment may be the key to managing HF with microvascular assessment. I suspect our wide degrees of variation in the absolute number as well as the change in PCD was because we enrolled patients with varying stages and degrees of HF. We contend that a patient with early HF, who has not developed the endothelial dysfunction in the microvasculature that may occur in those with more advanced disease, will be a better responder to nitroglycerin. The parameters encountered may differ significantly when compared to patients with more severe disease, such as those studied in the work of denUil [2]. Added to this complexity is the possibility that microvascular perfusion parameters and changes with treatment may differ in patients on chronic nitrates who may have down-regulated nitric oxide synthase. Unfortunately, this manuscript could not further explore these intricacies. Our patients who had poor perfusion parameters and later died in our study most likely had more advanced disease, and we will need larger numbers of patients to determine 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 is interesting that furosemide had any impact on microvascular perfusion, as the 2007 American College of Emergency Physicians Guideline specifically state standalone diuresis has not clinically been shown to be of benefit [3]. So, is PCD ready for clinical bedside management? No, but we hope to get there by assessing serial measurement and by incorporating other assessors of the microvasculature that have shown promise, such as tissue oxygenation [4]. If my colleague is curious regarding the repeated microvascular measurements as treatment is given to these patients as they are admitted and beyond, I would suggest not letting his subscription to the American Journal of Emergency Medicine lapse. Sincerely, Sébastien Champion, MD Réanimation médicale et toxicologique, Lariboisière Hospital 2 rue A. Paré, 75010 Paris, France E-mail address: [email protected] http://dx.doi.org/10.1016/j.ajem.2013.11.041