Accepted Manuscript. Mitchell S. Buckley, Robert MacLaren. S (17)30641-X doi: /j.jcrc Reference: YJCRC

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1 Accepted Manuscript Concomitant vasopressin and hydrocortisone therapy on shortterm hemodynamic effects and vasopressor requirements in refractory septic shock Mitchell S. Buckley, Robert MacLaren PII: S (17)30641-X DOI: doi: /j.jcrc Reference: YJCRC To appear in: Revised date: Accepted date: ###REVISEDDATE### ###ACCEPTEDDATE### Please cite this article as: Mitchell S. Buckley, Robert MacLaren, Concomitant vasopressin and hydrocortisone therapy on short-term hemodynamic effects and vasopressor requirements in refractory septic shock, (2017), doi: / j.jcrc This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

2 Concomitant Vasopressin and Hydrocortisone Therapy on Short-Term Hemodynamic Effects and Vasopressor Requirements in Refractory Septic Shock Running Head: Vasopressin and Hydrocortisone Effects in Septic Shock Mitchell S. Buckley, Pharm.D., FCCM, FCCP, BCCCP 1 Robert MacLaren, Pharm.D., MPH, FCCM, FCCP 2 1 Banner - University Medical Center Phoenix, Department of Pharmacy, 1111 E. McDowell Road, Phoenix, AZ USA University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, E. Montview Blvd. V , Aurora, CO USA Keywords: hydrocortisone, sepsis, septic shock, vasopressin Word Count (excluding abstract, tables, references, figures): 3572 Abstract Word Count: 200 Financial support: No financial and material support was provided for this article. Conflict of interest: None Poster Presentation: This original research will be presented as a poster presentation at the 2017 American College of Clinical Pharmacy Annual Meeting in October Corresponding author: Mitchell S. Buckley, Pharm.D., FASHP, FCCM, FCCP, BCCCP Clinical Pharmacy Specialist Critical Care Banner University Medical Center Phoenix Department of Pharmacy 1111 E. McDowell Rd. Phoenix, AZ Office: Mitchell.buckley@bannerhealth.com 1

3 Abstract Purpose The objective of this study was to evaluate the short-term hemodynamic effects as well as vasopressor requirements with concomitant vasopressin (AVP) and hydrocortisone (HCT) compared to either agent alone in refractory septic shock. Materials and Methods This was a retrospective, cohort study conducted in adult septic shock patients. Patients received continuous infusion AVP at 0.04 units/min and/or HCT mg intravenous daily in divided doses for refractory septic shock. Refractory septic shock was defined as systolic or mean blood pressure (MAP) of <90 mmhg or <70 mmhg, respectively, despite fluid resuscitation and requiring norepinephrine. Results A total of 300 patients were evaluated. The rate of achieving a response (norepinephrine dose reduction by 50% without any decrease in MAP) at 4 hours from baseline was significantly higher in patients receiving concomitant AVP/HCT (88.5%) compared to HCT alone (62.3%) or AVP alone (72.9%) (p=0.0005). The AVP/HCT group had higher response rates over the HCT and AVP monotherapy groups at 12 (p=0.052) and 24 hours (p=0.036). Multivariate regression showed combination therapy to be independently associated with response at 4 hours. Conclusions Concomitant AVP and HCT was associated with an immediate, additive catecholamine-sparing effect over either agent alone in patients with refractory septic shock. 2

4 Introduction Severe sepsis and septic shock remains a significant problem in the critically ill patient population despite recent therapeutic advances. The incidence has been estimated at 751,000 cases annually with over 50% of these patients requiring admission to the intensive care unit (ICU) [1]. Sepsis has been identified as one of the leading causes of death in non-cardiovascular ICUs [2]. The mortality rate of severe sepsis and septic shock ranges from 30-60% [1-2]. The impact on healthcare resources and costs is also concerning. Total ICU costs associated with the management of severe sepsis has been estimated at $4651 (2014 U.S. dollars) per day [3]. Several therapeutic strategies are currently available in the management of septic shock [4]. Appropriate and timely antimicrobial therapy remain cornerstones in the initial management [4]. In addition, hemodynamic support with fluid resuscitation, inotropic therapy, and adrenergic vasopressor agents are often employed [4]. Although several novel therapies are either currently available or undergoing clinical trials for the treatment of septic shock (e.g. extracorporeal therapy, immunoglobulins, interferon-beta, etc.), no specific therapy has consistently demonstrated improved clinical outcomes [4-5]. However, a recent study has shown promise in possibly preventing progressive organ dysfunction in septic shock patients with the early administration of intravenous vitamin C, hydrocortisone, and thiamine [6]. The use of hydrocortisone (HCT) and arginine vasopressin (AVP) are viable options for patients with refractory septic shock [4]. Endogenous cortisol and vasopressin are necessary to maintain cardiovascular homeostasis [7-11]. However, relative deficiencies in endogenous serum concentrations of cortisol, vasopressin, or both have been found in septic shock patients, which may contribute to vasopressor-dependent, refractory septic shock [7-11]. Studies evaluating low-dose HCT in septic shock patients have demonstrated an improvement in hemodynamics, a decrease in vasopressor requirements, and a possible survival benefit although these findings are inconsistent [12-23]. Adjunctive AVP therapy in septic shock has also shown a beneficial impact on hemodynamics and vasopressor-sparing effects [24-33]. However, AVP has not been shown to impact mortality [30,33]. Although HCT and AVP have separately shown beneficial effects in septic shock, the concomitant use of both agents remains controversial. Animal models have shown variable effects of AVP and corticosteroid therapy on the hypothalamic-pituitary-adrenal axis and serum vasopressin concentrations, respectively [34-43]. Corticosteroid administration may exhibit additive, inhibitory or equivocal effects on serum vasopressin concentrations, while AVP therapy has more consistently increased basal corticosterone concentrations [34-43]. Human clinical trials have not 3

5 corroborated any significant changes in serum cortisol or vasopressin concentrations with HCT or AVP administration [44-46]. Despite frequent use in clinical practice, few studies have investigated the clinical effects of concomitant AVP/HCT in septic shock [46-49]. Lower mortality rates have been associated with adjunctive corticosteroid and AVP therapy although these findings were inconsistent [46-48]. Also, combination therapy may decrease the duration of vasopressor support [46-47]. Only one study evaluated the impact of concomitant AVP/HCT vs. AVP alone on mean arterial pressures (MAP), which found no significant difference in MAP between study groups [46]. Unfortunately, all of these studies compared patients receiving concomitant AVP/HCT and AVP monotherapy without any direct comparison to only HCT therapy. Therefore, the purpose of this study was to evaluate the short-term hemodynamic effects as well as vasopressor requirements between concomitant AVP and HCT compared to either agent alone in septic shock patients. Materials and Methods Patients and Study Design This was a retrospective, cohort study conducted at a 700-bed Level I Trauma Center, major quaternary care University Hospital (Phoenix, AZ) with an average daily admission rate of about 94 patients and >34,000 adult inpatient admissions per year. Adult septic shock patients receiving AVP and/or HCT therapy were evaluated from January 1, 2012 to December, 31, Inclusion criteria consisted of the following: (1) 18 years of age; (2) known or suspected infection; (3) refractory shock [systolic blood pressure (SBP) <90 mmhg or MAP <70 mmhg despite fluid resuscitation and requiring norepinephrine]; and (4) HCT mg/day intravenous monotherapy, AVP continuous infusion at a rate of 0.04 units/minute monotherapy, or concomitant AVP/HCT initiated <24 hours after shock onset. Patients with concomitant therapy were only included if the second agent was administered <24 hours after the first agent was started irrespective of whichever drug (HCT or AVP) was initiated first. Patients were excluded if AVP and/or HCT were used for purposes other than the management of septic shock; shock syndrome possibly attributed to other non-sepsis related causes (i.e. cardiogenic or neurogenic shock); or AVP infusion was administered for <2 hours as there may have been questionable need or impending mortality. Following Institutional Review Board approval, patients meeting criteria were identified through the electronic medical record database. Patients were categorized into one of three study cohorts: (1) HCT only; (2) AVP only; or (3) concomitant AVP/HCT groups. Patients were screened during the study period until 100 patients 4

6 were identified into all three study groups. Groups were not matched or aligned according to underlying acuity of illness as all patients had refractory septic shock and were consecutively chosen for inclusion. Pertinent demographic and clinical data were collected including age, gender, weight, primary diagnoses, significant past medical history (e.g. diabetes mellitus, heart failure, cancer, or end-stage renal/liver disease), need for renal replacement therapy, volume of fluids administered over a 4-hour period preceding baseline, and documented infection (organism and site of infection). Certain medications administered at baseline were also documented such as broad-spectrum antimicrobials as well as insulin and norepinephrine infusion rates. Hemodynamic data (MAP) and norepinephrine dosage (mcg/min) requirements were assessed at 8 hours before baseline, baseline and at 1, 2, 4, 8, 12, 16, and 24 hours following the initiation of HCT, AVP, or concomitant AVP/HCT therapy. Clinical outcomes including mortality rate, length of stay in the ICU and overall hospitalization as well as disposition status (discharged home or inter-facility transfer) for surviving patients were also collected. Definitions Baseline was defined as the time upon initiation for either HCT or AVP as documented in the medical chart for when the infusion was started or when the first dose was administered. In the concomitant AVP/HCT group, baseline was considered at the time when the second adjunctive agent was started, irrespective of which agent was first started. Patients in all study groups were categorized as responders or non-responders to HCT and/or AVP therapy. For the primary outcome, responders were defined as patients with 50% norepinephrine dose reduction at 4 hours from baseline without any reduction from baseline MAP, while non-responders were all patients not achieving at least a 50% norepinephrine dose reduction or the MAP was reduced from baseline irrespective of the norepinephrine infusion rate. Despite the lack of a universally accepted definition for response, the investigators determined this objective criteria based on previously published reports [50-53]. To the best of our knowledge, only one study defined treatment efficacy (i.e. response ) a priori by the prevalence and extent of an increase in MAP within 30 minutes after starting AVP infusion and by the extent of norepinephrine dose decreases between 30 minutes and 24 hours [50]. Unfortunately, this study did not report % change from baseline for MAP or norepinephrine dose reductions. Although other reports did not define response a priori, several studies evaluating the impact of AVP on norepinephrine dose requirements consistently observed decreases 50% at various time periods within 24 hours of initiating AVP infusions [51-53]. However, these studies showed minimal changes in MAP (<10%) or no change at all from baseline [51-53]. Therefore, based on these study observations, we 5

7 determined 50% norepinephrine dose decreases from baseline without any decrease in MAP as a response. As secondary outcomes, response at 12 and 24 hours after initiation of the study drugs was also assessed. Organ dysfunction was defined using objective criteria as previously published [54]. Statistical Analysis A sample size of 100 patients in each study group was determined to ensure at least 65 patients per group could be evaluated at 4 hours. Assuming a desired response rate difference of 25% between any group, 65 patients per group would have 80% power assuming an alpha of as adjusted for multiple comparisons. The 4-hour evaluation period was chosen by the investigators based on previously published reports of vasopressin s immediate effects on MAP and norepinephrine requirements [50-51]. The primary objective of the study was to evaluate the response rate in the AVP/HCT group compared to either agent alone at 4 hours from baseline. Secondary analyses included response at 12 and 24 hours after initiation of the study drugs and comparative assessments of MAP and norepinephrine requirements of responders and non-responders over 24 hours from baseline. Mortality rates, length of ICU and hospital stay, and organ dysfunction observed in each study group were compared as well. Univariate analyses of groups used Chi square test for categorical variables and Student t-test or analysis of variance for continuous variables. Parameters with p-values 0.1 were evaluated for effect on response using backward multivariate logistic regression analysis. These data are presented as odds ratio (OR) and 95% CI. Analysis of variance with Tukey s test for post-hoc analysis assessed multiple comparisons to the -8 hour time point for hemodynamic data and rates of norepinephrine administration. A p-value of <0.05 was considered statistically significant using JMP Statistical Software, version 13 (SAS Institute Inc, Cary, NC, 2016). Results A total of 936 patients were identified during the study period and screened for inclusion criteria. A total of 300 patients (100 patients in each of the study groups) were included in the analysis. The overall study population s mean age was 50.4 ± 22.6 years with sepsis being the most common primary diagnosis (43.6%). Most patient characteristics were similar among the three study groups (Table 1). However, significant differences between groups were observed for severity of illness (e.g. SOFA score, renal replacement therapy, and the use of high-dose norepinephrine) at baseline. 6

8 The responder rate was significantly higher in the concomitant AVP/HCT group over either HCT or AVP monotherapy at 4 hours (Table 2). The responder rate in the combination group was significantly higher than the other groups at 24 hours and trended towards significance at 12 hours. No significant differences in MAP between responders and non-responders were observed except during the first two hours after baseline with responders experiencing a significantly higher MAP compared to those that did not respond (Table 3). The mean norepinephrine dose was significantly lower at every time interval evaluated for responders compared to nonresponders within the first 24 hours (Table 3). Norepinephrine dose requirements tended to decrease over time (although not statistically different) in responders but significantly increased in non-responders (Table 3). Univariate comparison of responders versus non-responders at 4 hours showed differences between groups (Table 4). Responders were more likely to be in the AVP/HCT group, older, male, and higher SOFA scores at baseline. Also, responders were more likely to be receiving high-dose norepinephrine (>15 mcg/min), but less likely to require renal replacement therapy at baseline. Parameters associated with response at four hours based on multivariate logistic regression analysis included treatment group, age, and SOFA score (Table 5). Combination AVP/HCT was a predictor of response over either monotherapy group at the 4 hour time period. Also, the AVP/HCT group had a significantly higher likelihood of response over the HCT group at 12 hours and over the AVP group at 24 hours (Table 5). Overall mortality was 42.3% without any significant differences among all study groups (Table 6). The majority of surviving patients were transferred to long-term acute care hospitals at hospital discharge for all groups. The mean ICU and hospital length of stay for the entire study population were 6.0 ± 3.6 and 10.1 ± 4.1 days, respectively. The AVP/HCT group had significantly longer ICU and overall hospital stays compared to the other groups. No differences were observe for any of these outcomes when comparing responders to non-responders at 4 hours. Discussion The aim of this retrospective, cohort study was to describe the short-term effects of concomitant AVP/HCT on MAP and norepinephrine requirements. The findings suggest concomitant AVP/HCT may have an immediate, additive effect as a catecholamine-sparing agent compared to either agent alone in adult, refractory septic shock 7

9 patients. The higher response rate with combination therapy over monotherapy was observed within 2 hours from baseline and sustained up to 24 hours. Interestingly, a higher response rate was observed with combination AVP/HCT despite being more critically ill (i.e. more patients were on high-dose norepinephrine, renal replacement therapy, and higher SOFA scores at baseline); however, only combination therapy, increasing age and higher SOFA scores were independently associated with hemodynamic response. The clinical significance of this study suggests providers may observe a significant reduction in norepinephrine doses while preserving MAP within 4 hours of initiating AVP/HCT therapy for refractory septic shock, while alternative strategies may be considered if not responding within this time period. Several studies investigating the role of low-dose HCT in septic shock have demonstrated beneficial catecholamine-sparing effects [13,15-16,21,55]. Prospective, randomized, placebo-controlled trials have consistently reported similar results suggesting HCT significantly reduces the median time to vasopressor withdrawal by about 2-3 days compared to placebo [13,15-16,21]. Also, a recent meta-analysis found 7- and 28-day shock reversal rates were significantly higher with HCT over control groups [55]. Unlike our study, these studies did not report the short-term (i.e. 24 hours of initiating therapy) effects of HCT on vasopressor requirements, but rather the median time to catecholamine cessation of therapy or probability of shock reversal. One prospective, randomized trial found HCT significantly lowered the percent change of vasopressor doses with HCT at 12 hours from baseline and every 12-hour interval up to an 84-hour evaluation period (p<0.001) [12]. However, the investigators did not report the exact percent change values at any of the time intervals assessed; thus, making any comparison with our current study not possible [12]. Several studies have investigated the short-term effect of AVP on vasopressor requirements during septic shock with conflicting results [26,28,35,44]. Patel et al, showed AVP significantly decreased norepinephrine requirements from 25.0 mcg/min to 5.3 mcg/min at 4 hours from baseline while maintaining MAPs [26]. This result was similar to our study in that the vast majority of patients had norepinephrine doses reduced by 50% at 4 hours from baseline as well. The median AVP infusion rate in their study was 0.06 units/min ( ) and titrated to effect, while our evaluation employed a constant rate of 0.04 units/min in all patients based on current institutional practice. This study evaluated the norepinephrine rate of infusion at 4 hours from baseline after initiating AVP as the only time interval assessed during the study period (i.e. a one-time evaluation period rather than multiple time 8

10 intervals), which may be considered a major limitation; our study evaluated norepinephrine dose reductions by 50% over several time intervals over a 24-hour period to demonstrate sustained effects. Similar to Patel et al, Obritsch et al, showed adjunctive AVP reduced the hourly catecholamine administration by 25% while improving MAP by 15% one hour after initiating AVP [28]. However, the AVP infusion rate was titrated to a mean dosage regimen of 0.11 ± 0.17 units/min [28]. Two other studies found significant reductions in norepinephrine doses at 24 and 48 hours from baseline with AVP [35,44]. However, both of these studies did not observe any immediate effects of AVP on norepinephrine requirements at 1, 6, and 12 hours from baseline, which is in contrast to our findings [35,44]. The VASST trial reported norepinephrine infusion rates were significantly lower in the AVP compared to the norepinephrine group over the initial 4 days (p<0.001), but the investigators did not report specific values or disclose the specific time intervals that were assessed [30]. The impact of concomitant AVP/HCT on hemodynamics and vasoactive support requirements from previously published studies have conflicting results [46-48]. A retrospective, case-control study found no significant differences in the median time to vasopressor withdrawal between concomitant AVP/HCT and AVP only groups (65 vs. 20 hours, p=0.09) [47]. Also, a post hoc substudy of the VASST trial failed to demonstrate any significant differences between AVP/HCT and AVP alone groups in reducing norepinephrine requirements [48]. However, a prospective, open-labeled, randomized controlled pilot study evaluated combination AVP/HCT compared to AVP alone on time to wean the AVP infusion as well as supplemental norepinephrine requirements. The duration of AVP and norepinephrine infusions were 3.1 days (95% CI, 1.1 to 5.1, p=0.001) and 2.0 days (95% CI, -7.0 to 0.0, p=0.015), respectively, shorter in patients receiving AVP/HCT compared to AVP alone [46]. The only study investigating the effects of concomitant AVP/HCT on MAP found no significant differences in patients administered AVP with or without HCT [46]. Our study found the vast majority of patients (88.5%) achieved significant reductions in norepinephrine dosage requirements by 50%, while maintaining MAP with concomitant AVP/HCT over either agent alone within the first 24 hours of therapy. Several important differences among these studies should be noted when interpreting their results. Two studies utilized AVP as the initial catecholamine [46-47]. Vasopressin was the initial vasoactive agent employed in all randomized patients for one study [46], while the other reported AVP as the initial agent for shock for almost 50% of patients in each study arm [47]. These investigators also disclosed AVP was the only vasopressor agent for 28.6% and 47.6% of patients in the concomitant AVP/HCT and AVP alone groups, respectively [47]. Although the median dose of AVP in one study was

11 units/min, the infusion rates ranged from about 0.02 to 0.08 units/min in both study groups [47]. Gordon et al, titrated AVP up to a maximum rate of 0.06 units/min based on hemodynamic response prior to initiating norepinephrine [46]. Higher AVP doses (e.g units/min) in septic shock may be more effective in reversing cardiovascular failure than physiologic (i.e units/min) replacement doses, but the risk of adverse events may be increased [32,56]. Higher doses of AVP (i.e. pharmacologic rather than physiologic replacement) as well as its role as the initial and primary vasopressor in septic shock may not reflect current standards of practice. This is approach is currently not recommended in the 2016 Surviving Sepsis Campaign Guidelines [4]. Variability in AVP dosing may account for differences observed on hemodynamics and catecholamine requirements. Despite its potential advantage, the safety and efficacy of high-dose AVP should be evaluated by more robust studies before becoming universally accepted as standard of care. Our study more closely reflects the pragmatic use of AVP and HCT as adjunctive therapies at set dosage regimens that reflect physiologic replacement rather than dosage regimens that are titrated to MAP. This is consistent with the clinical practice of managing septic shock and aligns with current guideline recommendations in regards to dosing and roles in therapy (i.e. refractory septic shock without adequate hemodynamic response despite fluid resuscitation with norepinephrine as the initial, primary vasoactive agent).[4]. Another distinct aspect of our study was the comparison between HCT alone and AVP alone with concomitant AVP/HCT groups; other previously published reports only conducted comparisons with an AVP alone control arm [46-48]. Whether a dose-response interaction of AVP and HCT existed could not be evaluated. Ideally the minimum dose of each agent would be utilized to minimize the potential for adverse events and costs, especially considering the rising cost of AVP. There were several limitations of this study that should be noted. This was a single-center, retrospective evaluation of a diverse ICU population. Severity of illness was not uniform based on SOFA scores, need for renal replacement therapy, and high-dose norepinephrine requirements, which may potentially impact response to therapy irrespective of the study group. Interestingly, the concomitant AVP/HCT group had significantly higher SOFA scores as well as more patients with renal replacement therapy and high-dose norepinephrine, yet this group demonstrated a more profound response and combination therapy was independently associated with response. Although we reported clinical outcomes (mortality and length of stay), this study was not designed to detect any differences in these outcomes and not the primary focus of our analysis. The aim of this study was to evaluate shortterm impact on norepinephrine requirements over a 24-hour period. It is important to recognize response used in 10

12 this study is not a universally accepted definition and the clinical application of this might be controversial. Nonetheless, reducing norepinephrine rates by 50% may serve as a surrogate, anecdotal marker of response in managing refractory septic shock. In addition, adverse drug events (ADEs) were not evaluated. Most ICU patients have numerous confounding variables making the delineation of drug-induced events challenging despite using validated ADE causality instruments (e.g. Naranjo scale, etc.). Furthermore, large randomized, controlled trials have not suggested HCT or AVP results in significantly higher ADE rates [19,21,30]. Also, invasive hemodynamic variables (e.g. cardiac index, pulmonary capillary wedge pressure, systemic vascular resistance, etc.) and AVP serum concentrations were not measured since this is not routine clinical practice at the study site. However, we believe this should not severely limit the interpretation of our results. The complex interaction between AVP and HCT remains controversial and the association with AVP serum concentrations with its clinical significance on outcomes has not been well established [56]. Conclusion The role of concomitant AVP and HCT in the critically ill remains elusive given conflicting results and potential interactions between these two agents. Critically ill patients are commonly administered concomitant AVP and HCT as adjunctive therapy in refractory septic shock despite the paucity of data. This study found concomitant AVP and HCT was associated with an immediate, additive catecholamine-sparing effect over either agent alone in patients with refractory septic shock as well as independently associated with hemodynamic response. 11

13 Acknowledgements None 12

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19 Table 1. Patient Characteristics Variables HCT (n=100) AVP (n=100) AVP/HCT (n=100) Age (years) A 62.2 ± ± ± 13.4 Male (%) B Weight (kg) 88 ± ± ± 24.9 Primary diagnosis, n (%) Sepsis Abdominal Pulmonary Urogenital Surgery / Trauma Neurologic Other Volume of Fluids Administered within 4 hours of baseline (ml) 44 (44) 5 (5) 24 (24) 8 (8) 5 (5) 10 (10) 4 (4) 46 (46) 7 (7) 24 (24) 5 (5) 6 (6) 8 (8) 4 (4) 41 (41) 7 (7) 26 (26) 6 (6) 2 (2) 10 (10) 8 (8) ± ± ± SOFA score C 12.2 ± ± ± 2.8 Renal replacement therapy 20 (20) 28 (28) 43 (43) at baseline, n (%) D Norepinephrine dose 15 mcg/minute at baseline, n (%) E Insulin infusion at baseline, n (%) Comorbidities, n (%) Atrial fibrillation Cancer Chronic kidney disease Congestive heart failure Coronary artery disease COPD CVA Dementia Diabetes HIV/AIDS Hypertension Liver disease Culture positive site, n (%) Abdomen Blood Respiratory Urine Wound Negative Microbes, n (%) Gram positive Gram negative Fungus Clostridium difficile 22 (22) 60 (60) 83 (83) 31 (31) 42 (42) 33 (33) 16 (16) 20 (20) 24 (24) 11 (11) 23 (23) 13 (13) 8 (8) 6 (6) 41 (41) 1 (1) 53 (53) 16 (16) 3 (3) 40 (40) 18 (18) 33 (33) 10 (10) 28 (28) 3 (3) 10 (10) 23 (23) 3 (3) 7 (7) 5 (5) 4 (4) 3 (3) 44 (44) 2 (2) 54 (54) 14 (14) 6 (6) 45 (45) 31 (31) 14 (14) 18 (18) 20 (20) 7 (7) 14 (14) 39 (39) 10 (10) 21 (21) 11 (11) 10 (10) 2 (2) 43 (43) 0 59 (59) 38 (38) 6 (6) 50 (50) 50 (50) 20 (20) 16 (16) 14 (14) 30 (30) 37 (37) 8 (8) 10 (10) 38 (38) 39 (39) 11 (11) 2 (2) 44 (44) 40 (40) 26 (26) 11 (11) 18

20 Data presented as mean ± SD unless otherwise noted. AVP = vasopressin; COPD = chronic obstructive pulmonary disease; CVA = cerebrovascular accident; HCT = hydrocortisone; HIV/AIDS = human immunodeficiency virus / acquired immunodeficiency syndrome; SOFA = sequential organ failure assessment. A, p=0.04 by ANOVA. B, p=0.024 by Chi Square with two degrees of freedom. C, p< by ANOVA. D, p= by Chi Square with with two degrees of freedom. E, p< by Chi Square with with two degrees of freedom. 19

21 Table 2. Comparison of response rate among study groups Variable Rate Response at 4 Hours, p= Responder Non-responder HCT (n=67) 42 (62.3) 25 (37.3) AVP (n =85) 62 (72.9) 23 (27.1) AVP/HCT (n=96) 85 (88.5) 11 (11.5) Response at 12 Hours, p=0.052 HCT (n=57) 29 (50.1) 28 (49.9) AVP (n =79) 37 (46.8) 42 (53.2) AVP/HCT (n=88) 57 (64.8) 31 (35.2) Response at 24 Hours, p=0.036 HCT (n=53) 17 (32.1) 36 (67.9) AVP (n =67) 28 (41.8) 39 (58.2) AVP/HCT (n=69) 38 (54.4) 31 (45.6) Data presented as n (%). AVP = vasopressin; HCT = hydrocortisone; NS = not statistically significant. A Chi square with two degrees of freedom comparing response rates between groups. 20

22 Table 3. Comparison of responders vs. non-responders at four hours for mean arterial pressure and norepinephrine dose requirements over time. Variables Time period Mean Arterial -8hrs Baseline 1hr 2hrs 4hrs 8hrs 12hrs 24hrs Pressure (mmhg) Responders 68.2± ± ± ± ± ± ± ±11.7 Nonresponders 65.3± ± ±11.9 A 67.9±11.1 B 67± ± ± ±12.1 Norepinephrine dose (mcg/min) Responders 13.2± ±14.3 C 15.6± ± ± ± ± ±6.3 Nonresponders 20.6±14.4 D 28.3±18.3 D,E 28.2±18.5 D,E 29.7±20.1 D,F 29.6±20.3 D,G 27.5±20 D,H ±19 D,I 20.2±18.1 D Data presented as mean ± SD. A, p=0.01 vs. responders. B, p=0.004 vs. responders. C, p<0.001 vs. -8hrs. D, p<0.001 vs. responder. E, p=0.022 vs. -8hrs. F, p=0.027 vs. -8hrs. G, p=0.004 vs. -8hrs. H, p=0.031 vs. -8hrs. I, p =0.024 vs. -8hrs. A, B, C, D by Student t test. E, F, G, H, I by analysis of variance with Tukey s test for post-hoc analysis with multiple comparisons to -8hrs. 21

23 Table 4. Univariate analyses of patient characteristics by responder group at 4 hours Variables Responders (n=189) Non-Responders (n=59) Group, n (%) A HCT 42 (22.2) AVP 62 (32.8) AVP/HCT 85 (45) 25 (42.4) 23 (38.9) 11 (18.6) Age (years) B 59.9 ± ± 13.8 Male (%) C 107 (56.6) 26 (44.1) SOFA score D 12.6 ± ± 3.7 Renal replacement therapy at 60 (31.7) 20 (37.7) baseline, n (%) E Norepinephrine dose 15 mcg/minute at baseline, n (%) F 138 (73) 35 (59.3) Data presented as mean ± SD unless otherwise noted. AVP = vasopressin; HCT = hydrocortisone; SOFA = sequential organ failure assessment. A, p= by Chi Square with two degrees of freedom. B, p=0.061 by Student t test. C, p=0.09 by Chi Square. D, p=0.001 by Student t test. E, p= by Chi Square. F, p=0.05 by Chi Square. 22

24 Table 5. Multivariate logistic regression predicting response Variable Odds ratio 95% CI P value 4 Hour Response AVP/HCT vs. HCT p=0.012 AVP/HCT vs. AVP p=0.01 HCT vs. AVP p=0.54 Age (each incremental year) p=0.01 SOFA score (each incremental p= point score) Male vs. female p=0.37 Need for RRT at baseline vs p=0.1 not High-dose NE at baseline vs p=0.1 not 12 Hour Response AVP/HCT vs. HCT p=0.015 AVP/HCT vs. AVP p=0.43 HCT vs. AVP p=0.26 Age (each incremental year) p=0.047 SOFA score (each incremental p= point score) Male vs. female p= Need for RRT at baseline vs p=0.37 not High-dose NE at baseline vs p=0.51 not 24 Hour Response AVP/HCT vs. HCT p=0.07 AVP/HCT vs. AVP p=0.046 HCT vs. AVP p=0.52 Age (each incremental year) p=0.1 SOFA score (each incremental p= point score) Male vs. female p=0.026 Need for RRT at baseline vs p=0.59 not High-dose NE at baseline vs. not p=0.93 AVP = vasopressin; CI = confidence interval; HCT = hydrocortisone. Multivariate Logistic Regression including group, gender, age, NE dose 15 mcg/minute at baseline, SOFA, RRT at baseline. 23

25 Table 6. Patient Outcomes Variables HCT (n=100) AVP (n=100) AVP/HCT (n=100) Length of stay, days ICU A 8 ± 6.1 Hospital B Discharge status, n (%) Home Skilled nursing facility transfer 11 ± (30) 43 (43) 9 ± ± (18) 37 (37) 11 ± ± (15) 55 (55) Mortality, n (%) 27 (27) 45 (45) 30 (30) Data presented as mean ± SD unless otherwise noted. AVP = vasopressin; HCT = hydrocortisone; ICU = intensive care unit. A, p=0.013 by ANOVA. B, p=0.04 by ANOVA 24

26 Highlights Concomitant vasopressin and hydrocortisone may have an immediate, additive effect as a catecholamine-sparing agent compared to either agent alone in adult, refractory septic shock patients A higher rate of response (norepinephrine dosing requirements decreased by 50%, while maintaining goal mean arterial pressures) was observed in patients administered combination therapy over monotherapy achieved within 2 hours from initiation and sustained up to 24 hours Multivariate regression analyses showed combination therapy, higher SOFA scores, and increasing age to be independently associated with response at 4 hours 25