Evaluation of Vasopressin for Septic Shock in Patients on Chronic Renin-AngiotensinAldosterone System Inhibitors Beth L. Erwin, PharmD, BCCCP1; Michael A. Denaburg, PharmD, BCCCP1; Andrew B. Barker, MD2; Philip J. McArdle, MB, BCh, BAO, FCARCSI2; Samuel T. Windham, MD3; Charity J. Morgan, PhD4
Objectives: To compare the hemodynamic response in septic shock patients receiving vasopressin who were on chronic reninangiotensin-aldosterone system inhibitor therapy with those who were not. Design: Single-center, retrospective cohort study. Setting: Medical and surgical ICUs at a 1,100-bed academic medical center. Patients: Medical and surgical ICU patients with septic shock who received vasopressin infusion added to at least one concomitant vasopressor agent between January 2014 and December 2015, then divided into two cohorts: 1) patients who were on chronic renin-angiotensin-aldosterone system inhibitor therapy as outpatients and 2) patients who were not on chronic renin-angiotensinaldosterone system inhibitor therapy as outpatients. Interventions: None. Measurements and Main Results: Mean arterial pressure at 6 hours was 72.2 mm Hg in the renin-angiotensin-aldosterone system inhibitor group versus 69.7 mm Hg in the non–renin-angiotensin-aldosterone system inhibitor group (p = 0.298). There was no difference in mean arterial pressure at 1, 24, or 48 hours between groups. Total concomitant vasopressor requirements, based on norepinephrine equivalents excluding vasopressin, were significantly lower at 24
Department of Pharmacy, University of Alabama at Birmingham Hospital, Birmingham, AL. 2 Department of Anesthesiology, University of Alabama at Birmingham, Birmingham, AL. 3 Division of Acute Care Surgery, Department of Surgery, University of Alabama at Birmingham Hospital, Birmingham, AL. 4 Department of Biostatistics, University of Alabama at Birmingham, Birmingham, AL. This research was performed at University of Alabama at Birmingham Hospital, Birmingham, AL. The authors have disclosed that they do not have any potential conflicts of interest. Address requests for reprints to: Beth L. Erwin, PharmD, BCCCP, University of Alabama at Birmingham Hospital, JT 1728, 619 19th Street South, Birmingham, AL 35249. E-mail: [email protected] Copyright © 2017 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved. DOI: 10.1097/CCM.0000000000002729 1
Critical Care Medicine
hours in the renin-angiotensin-aldosterone system inhibitor group versus the non–renin-angiotensin-aldosterone system inhibitor group (10.7 vs 18.1 µg/min, respectively; p = 0.007), but no significant differences were seen at the other time points assessed. There were no significant differences in ICU or hospital length of stay or mortality. Conclusions: There was no significant difference in the primary outcome of 6-hour mean arterial pressure in septic shock patients receiving vasopressin who were on chronic renin-angiotensinaldosterone system inhibitor therapy versus those receiving vasopressin who were not on chronic renin-angiotensin-aldosterone system inhibitor therapy. Renin-angiotensin-aldosterone system inhibitor patients had lower total concomitant vasopressor requirements at 24 hours compared with non–renin-angiotensin-aldosterone system inhibitor patients. (Crit Care Med 2017; XX:00–00) Key Words: angiotensin-converting enzyme inhibitors; angiotensin receptor antagonists; hemodynamics; renin-angiotensin system; shock; septic; vasopressins
S
epsis is a state of systemic inflammation that manifests in response to infection. Septic shock, defined as sepsis-induced hypotension refractory to fluid resuscitation (1), is a leading cause of death in the ICU, with documented mortality rates as high as 50–85% (2). Both the 2012 and the 2016 Surviving Sepsis Campaign guidelines recommend norepinephrine as the first-line vasopressor for management of septic shock, with a target mean arterial pressure (MAP) of 65 mm Hg (1, 3). The guidelines support the addition of low-dose vasopressin (at a rate of 0.03 [2016 guidelines] to 0.04 units/min [2012 guidelines]) to norepinephrine in order to reach target MAP or to limit norepinephrine requirements, but they do not favor its use as initial vasopressor therapy in this septic shock population (1, 3). One notable advantage of vasopressin in the management of septic shock is its ability to enhance vascular sensitivity to catecholamines (4). Another potential advantage is its organ-specific vasodilatory effects, which in contrast to catecholamines may provide some degree of pulmonary vasodilation (4). The sympathetic nervous system, renin-angiotensinaldosterone system (RAAS), and vasopressin system are all www.ccmjournal.org
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critical pathways involved in acute blood pressure regulation (5). Among these various mechanisms contributing to hemodynamic stability are hormones with vasoconstrictor properties, two of which are vasopressin and angiotensin II. Vasopressin, also known as “antidiuretic hormone,” is a neurohormone that is released from the posterior pituitary in response to increased plasma osmolality and decreased plasma volume (6). In states of shock, vasopressin acts on vascular V1 receptors to induce vasoconstriction and rapidly restore blood pressure (6). However, it has been noted that vasopressin levels in patients with septic shock are inappropriately low (7). Angiotensin II, a component of the RAAS, regulates plasma volume and MAP via direct arteriolar vasoconstriction and stimulation of aldosterone release to increase sodium reabsorption. In addition to its direct vasoconstrictive properties, angiotensin II acts on the CNS to promote the secretion of vasopressin (6), which is a mechanism of particular importance to the current study. RAAS inhibitors (RAASIs), such as angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), are medications commonly prescribed to treat various chronic diseases including hypertension, congestive heart failure, and ischemic heart disease. Because chronic RAAS inhibition compromises one of the three primary endogenous responses to low arterial pressures, the role of vasopressin as a regulator of vascular tone may be of greater importance in this patient population. Also, given the relative state of vasopressin deficiency that occurs in septic shock, in combination with inhibited angiotensin II-mediated secretion of vasopressin in patients on chronic RAASIs, it seems plausible that patients on chronic RAASI therapy who present with septic shock would have a more profound response to treatment with vasopressin compared with patients not on chronic RAASI therapy. Hasija et al (8) found that low-dose vasopressin was successful in preventing postoperative hypotension in patients undergoing coronary artery bypass graft (CABG) surgery who received the preoperative ACEI , ramipril. In another study, Meersschaert et al (9) concluded that when combined with terlipressin, a synthetic vasopressin analog, ephedrine was more effective at treating anesthesia-induced hypotension than ephedrine alone in patients on chronic ACEI therapy. Similarly, Boccara et al (10) found that the effects of terlipressin were more rapid than norepinephrine for maintaining blood pressure during general anesthesia in patients receiving RAASIs. The majority of published studies involving the use of vasopressin as a regulator of arterial pressure in patients on chronic RAASIs were conducted during the perioperative period in patients undergoing various surgical procedures. The investigators of the current study are not aware of any published literature regarding the effects of chronic RAAS inhibition on the hemodynamic response to vasopressin in the population of patients with septic shock. The investigators of this study hypothesized that patients receiving chronic RAASIs who developed septic shock would have a greater response to vasopressin infusion, as evidenced by increased MAPs and decreased concomitant vasopressor requirements, compared with septic shock patients not receiving chronic RAASI therapy. 2
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MATERIALS AND METHODS This research was approved by the University of Alabama at Birmingham Institutional Review Board. A retrospective chart review of medical and surgical patients with septic shock who received vasopressin infusion between January 1, 2014, and December 31, 2015, was conducted at a single 1,100-plus-bed academic medical center. The primary outcome assessed was MAP at 6 hours (T6) after vasopressin initiation (T0). Secondary outcomes included MAP at 1 hour (T1), 24 hours (T24), and 48 hours (T48) after vasopressin initiation; total concomitant vasopressor requirements at T1, T6, T24, and T48; ICU and hospital length of stay; and ICU and hospital mortality. Concomitant vasopressor doses were converted to norepinephrine equivalents using the following conversion originally adopted in the Vasopressin and Septic Shock Trial (11): norepinephrine (µg/min) = epinephrine (µg/min) = phenylephrine (µg/min)/10 = dopamine (µg/kg/min)/2. Patient Selection All medical and surgical ICU patients who received vasopressin infusion during the specified 2-year timeframe, as identified by the hospital’s electronic database, were assessed for inclusion in the current study. Patients were screened for exclusion criteria in the following order: age less than 19 years, pregnant, initiation of vasopressin greater than 5 days since admission, duration of vasopressin less than 6 hours, vasopressin rate less than 0.02 or greater than 0.04 units/min, initiation of another vasopressor agent within 24 hours after vasopressin initiation, not on another vasopressor for at least 1 hour prior to vasopressin initiation, initiation of a steroidal agent within 6 hours after vasopressin initiation, and indication other than septic shock. The following data were collected for each patient: age; gender; body mass index; medical versus surgical ICU admission; history of diabetes mellitus, hypertension, peripheral artery disease, chronic kidney disease, heart failure, or coronary artery disease; ICU death or discharge; hospital death or discharge; ICU length of stay; hospital length of stay; outpatient RAASI therapy (medication name and dose); vasopressin start time, stop time, and infusion rate; concomitant vasopressor requirements at the time of vasopressin initiation; concomitant use of vasopressors while receiving vasopressin; concomitant use of steroids; MAP at prespecified time points; and baseline Sequential Organ Failure Assessment (SOFA) score, lactate, and pH. History of outpatient RAASI therapy was determined by reviewing history and physical notes, reviewing the patient’s medication history that is documented for all patients upon admission when feasible, and reviewing the patient’s external prescription fill history which contains prescription records provided by community pharmacies and pharmacy benefits managers. Of note, patients who were on outpatient spironolactone, an aldosterone antagonist, were not included in the RAASI group since its effects on vascular tone are likely clinically insignificant. Invasive measurements for MAP were used when available. Vasopressin start time was determined based on the time the nurse scanned the infusion bag which charts XXX 2017 • Volume XX • Number XXX
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Online Clinical Investigation
the initiation time in the electronic medication administration record (MAR). Vasopressin stop time was determined by the time of order discontinuation or the time the infusion was documented at a rate of zero in the electronic MAR, whichever came first.
the time of vasopressin initiation, addition of another vasopressor within the first 24 hours after vasopressin initiation, and duration of vasopressin infusion less than 6 hours. Table 1 displays the patient demographics and baseline characteristics. Thirty-seven patients were receiving outpatient RAASI therapy, Statistical Analysis whereas 63 patients were not. Of the 37 patients on chronic A power analysis was conducted and revealed that 100 patients RAASI therapy, 26 patients were on an ACEI, and 11 patients would be needed to detect a between-group difference in MAP were on an ARB, with lisinopril being the most commonly increase from baseline (time of vasopressin initiation) to 6 used ACEI and losartan being the most commonly used ARB. No patients were receiving the renin inhibitor, aliskiren. No hours of 20%, with 80% power. For all analyses, a p value of patients received a RAASI dose while inpatient prior to startless than 0.05 was considered statistically significant. ing vasopressin therapy. Patients in the RAASI group were more Student’s t test was used for comparison of continuous data likely to be older than those in the non-RAASI group, with an (MAP, total vasopressor requirements, length of stay, etc.). The average age of 68 versus 60 years, respectively (p = 0.006). As Fisher exact test was used for comparison of categorical data expected, RAASI patients tended to have more preexisting con(preexisting conditions, mortality, etc.). For MAP and total concomitant vasopressor requirements, a linear mixed model was ditions, although hypertension was the only one that reached used to assess the effects of RAAS inhibition over time. Unless statistical significance (81% vs 54%; p = 0.006). There were no otherwise specified, data are expressed as mean ± sd. All statis- significant between-group differences in baseline SOFA score, tical analyses were conducted using SAS software, version 9.4 lactate, pH, or total vasopressor requirements at T0. At T0, 89.2% of RAASI patients were receiving norepi(SAS Institute, Cary, NC). nephrine, 13.5% receiving phenylephrine, and 5.4% receiving epinephrine. In the non-RAASI group, 98.4% of patients RESULTS were receiving norepinephrine, 6.3% receiving phenylephSubjects rine, and 4.8% receiving epinephrine at baseline. No patients During the 24-month study period, 596 patients were idenwere receiving dopamine at T0. Ninety-two percent of RAASI tified as having received vasopressin infusion, of which 100 patients and 90% of non-RAASI patients were receiving a sinmet inclusion criteria (Fig. 1). The most common reasons for gle vasopressor at T0, with the remainder of patients in each patient exclusion were hospitalization greater than 5 days at group receiving two vasopressor agents at T0. Baseline vasopressor requirements are listed in Table 1. Sixty-three percent of study patients had all MAPs measured invasively via an arterial catheter. Nineteen percent of patients had only noninvasive MAP measurements. Fourteen percent were changed from noninvasive to invasive MAP measurement within 24 hours from T0, whereas 4% were switched from invasive to noninvasive MAP measurement during this time period. The mean vasopressin duration among RAASI patients was 66.5 hours (median 48 hr) compared with a mean duration of 64.1 hours (median 39 hr) among non-RAASI patients. Ninety-five percent of RAASI patients remained on vasopressin at 24 hours and thus were included in the T24 analyses compared with 90% of patients in the non-RAASI group. Fifty-four percent of Figure 1. Patient selection. ACEI = angiotensin-converting enzyme inhibitor, ARB = angiotensin receptor RAASI patients were able to blocker, RAASI = renin-angiotensin-aldosterone system inhibitor. Critical Care Medicine
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TABLE 1.
Patient Demographics and Baseline Characteristics
Characteristics
RAASI
No RAASI
p
Age (yr), mean (sd)
67.5 (11.4)
59.7 (14.4)
0.006
Male gender, n (%)
24 (64.9)
34 (54)
0.287
28.6 (8.8)
0.873 0.799
Body mass index (kg/m2), mean (sd)
28.9 (5.9)
Location, n (%) Medical ICU
29 (78.4)
51 (81)
Surgical ICU
8 (21.6)
12 (19)
Hypertension
30 (81.1)
34 (54)
0.006
Diabetes
16 (43.2)
19 (30.2)
0.185
Heart failure
10 (27)
9 (14.3)
0.117
Coronary artery disease
10 (27)
13 (20.6)
0.463
Chronic kidney disease
14 (37.8)
14 (22.2)
0.093
1 (2.7)
1 (1.6)
0.701
8.8 (2.8)
8.6 (2.8)
0.759
7.30 (0.1)
7.29 (0.2)
0.748
4.4 (3.3)
4.2 (3.9)
0.862
107 (22)
105 (22)
0.723
70 (10.5)
67.2 (12.3)
0.243
One
34 (91.9)
57 (90.4)
0.999
Two
3 (8.1)
6 (9.5)
Norepinephrine
33 (89.2)
62 (98.4)
0.054
Phenylephrine
5 (13.5)
4 (6.3)
0.394
Epinephrine
2 (5.4)
3 (4.8)
0.214
Preexisting conditions, n (%)
Peripheral artery disease Sequential Organ Failure Assessment score, mean (sd) pH, mean (sd) Lactate (mg/dL), mean (sd) Heart rate (beats/min), mean (sd) Mean arterial pressure at time 0 (mm Hg), mean (sd) Vasopressor(s) utilized at time 0, n (%)
Vasopressor(s) used at time 0, n (%)
Vasopressor requirements at time 0 (µg/min), mean (sd) Norepinephrine
27.6 (12.2)
26.6 (12.4)
0.682
Phenylephrine
180 (125.5)
243.8 (96.6)
0.539
Epinephrine Total concomitant vasopressor requirements at time 0 (µg/min), mean (sd)
11 (1.4)
7.3 (4.6)
0.388
27.7 (14.1)
28.2 (14.3)
0.865
RAASI = renin-angiotensin-aldosterone system inhibitor.
be included in the T48 analyses versus 51% of non-RAASI patients. Steroids were initiated prior to vasopressin therapy in 27% of RAASI patients and in 22% of non-RAASI patients. Outcomes There was no significant difference between groups in the primary outcome of MAP at T6, with an average 6-hour MAP of 72.2 mm Hg in the RAASI group versus 69.7 mm Hg in the non-RAASI group (p = 0.298). No differences were found in the secondary outcomes of MAP at T1, T24, or T48 or total 4
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vasopressor requirements at T1, T6, or T48. However, lower total vasopressor requirements at T24 were observed in the RAASI group compared with the non-RAASI group (10.7 vs 18.1 µg/min, respectively; p = 0.007). There were no betweengroup differences in ICU mortality, hospital mortality, ICU length of stay, or hospital length of stay. Table 2 displays both the primary and secondary outcomes results. The results of the linear mixed model for MAP are displayed in Figure 2, which portrays the estimated average MAP for each group over time. There was a nonsignificant trend for subjects XXX 2017 • Volume XX • Number XXX
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Online Clinical Investigation
TABLE 2.
Primary and Secondary Outcomes RAASI, Mean (sd)
No RAASI, Mean (sd)
p
MAP at 1 hr (mm Hg)
74.7 (10.5)
71.4 (10.2)
0.128
MAP at 6 hr (mm Hg)
72.2 (10.9)
69.7 (11.8)
0.298
MAP at 24 hr (mm Hg)
75.4 (8.7)
71.4 (12.3)
0.095
MAP at 48 hr (mm Hg)
73.4 (8.9)
72 (11.4)
0.655
Concomitant vasopressor requirements at 1 hr (µg/min)
25.3 (14.9)
25.8 (13.5)
0.841
Concomitant vasopressor requirements at 6 hr (µg/min)
21.8 (13.7)
23.5 (13.6)
0.563
Concomitant vasopressor requirements at 24 hr (µg/min)
10.7 (10.9)
18.1 (13.4)
0.007
Concomitant vasopressor requirements at 48 hr (µg/min)
9.4 (14)
13 (13.7)
0.356
ICU
10.6 (9.9)
11.8 (12.7)
0.631
Hospital
19.3 (18.2)
16.1 (14.4)
0.341
ICU
45.9
55.6
0.353
Hospital
48.6
65.1
0.107
Outcomes
a
Length of stay (d)
Mortality (%)
MAP = mean arterial pressure, RAASI = renin-angiotensin-aldosterone system inhibitor. a Primary outcome.
receiving RAASIs to have higher MAPs (p = 0.072) during this time period. The interaction between RAAS inhibition and time was not significant (p = 0.931). Figure 3 displays total vasopressor requirements over 48 hours, which decreased over time for both groups. RAASI patients had significantly lower total vasopressor requirements (p = 0.003). The interaction between RAAS inhibition and time trended toward significance (p = 0.056), indicating that patients on chronic RAASI therapy may have had a faster decrease in total vasopressor requirements compared with patients not on chronic RAASI therapy.
DISCUSSION
Figure 2. Mean arterial pressure from T0 to T48. RAASI = reninangiotensin-aldosterone system inhibitor.
Figure 3. Total concomitant vasopressor requirements from T0 to T48. RAASI = renin-angiotensin-aldosterone system inhibitor.
Critical Care Medicine
The study by Hasija et al (8) of prophylactic vasopressin in patients receiving preoperative ramipril undergoing CABG surgery found that of the patients who continued ramipril until the morning of surgery, those who received prophylactic vasopressin had higher MAPs after the termination of cardiopulmonary bypass and also had lower total vasopressor requirements than those who did not receive vasopressin. Although the current study did find similar results in regard to reduced total vasopressor requirements at 24 hours after
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vasopressin initiation in the RAASI group, it is difficult to directly compare the two studies given the different patient populations studied, as well as the impact of anesthesia on MAP and vasopressin response in the study by Hasija et al (8). Similarly, Meersschaert et al (9) conducted a randomized, crossover, double-blind study comparing terlipressin plus ephedrine versus ephedrine alone in the treatment of anesthesia-induced hypotension and found that patients with a partially blocked endogenous response to hypotension, such as those on an ACEI, had fewer second hypotensive episodes, a shorter duration of hypotension, and lower median doses of ephedrine. Again, the effects of anesthesia on the sympathetic nervous system’s ability to contribute to MAP regulation would confound any true comparison of these results to the current study. The study by Boccara et al (10) was also conducted in the operative arena where anesthesia was used. The results of the current study focus on the response to vasopressin infusion in patients on chronic RAASIs outside of the operative arena, specifically in patients with septic shock. The current study has limitations. Given the retrospective design of the study, determination of outpatient RAASI therapy relied upon documentation in the electronic medical record (EMR). Neither adherence to outpatient therapy nor time of last RAASI dose was able to be confirmed. In addition, EMR documentation was used to determine vasopressor start times and infusion rates, as nurses were allowed to titrate vasopressors (other than vasopressin) to obtain target MAP based on physician-defined variables. MAP at T6 was chosen as the primary endpoint with concomitant vasopressor requirements as a secondary endpoint; however, future studies may consider assessing concomitant vasopressor requirements as the primary endpoint given that nursing documentation of MAP may succeed a titration in concomitant vasopressor doses. The study was not powered to detect a difference in the clinical endpoints of length of stay and mortality. It is worth noting that source of infection, culture data, antibiotic therapy, fluid administration, vasopressin serum levels, and adverse effects were not assessed. It is possible that physician preference led to the initial addition of vasopressin to a select group of patients with septic shock given the nonrandomized nature of the study. However, excluding patients for whom vasopressin was chosen as the first-line vasopressor minimized this type of bias and allowed for evaluation of only those patients who were managed hemodynamically in accordance with the 2012 Surviving Sepsis Campaign guidelines. Because this study included only medical and surgical ICU patients with septic shock, these results cannot be generalized to other patient populations. The higher percentage of patients with hypertension, diabetes, heart failure, and chronic kidney disease in the RAASI group is expected given the indications for RAASIs. These differences are unlikely to have impacted the outcome given the similar baseline SOFA scores between groups. Also, one cannot rule out the possibility that patients who are on chronic RAASI therapy have a common underlying pathophysiologic process that led to the decreased vasopressor requirements at 24 hours after 6
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vasopressin initiation, with the outpatient initiation of RAASI therapy serving only as a surrogate marker for this underlying process. Because this study was nonrandomized with a relatively small sample size, the nonsignificant p values in baseline characteristics do not ensure similarity between groups. One major strength of the current study is the inclusion of patients who were on RAASI therapy for any indication, which allows for generalizability of the results to patients with a variety of disease states including hypertension, heart failure, and chronic kidney disease. Second, the study is strengthened by its focus on patients with septic shock since other types of shock are not associated with the same level of endogenous vasopressin depletion, and thus the addition of vasopressin might not play as big of a role in patients on chronic RAASIs. And third, this study found several trends in secondary endpoints that might have proven significant with adequate power, such as a trend toward reduced vasopressor requirements over time and a trend toward lower overall mortality in RAASI patients. Although 6-hour MAP was not found to be statistically significantly higher in the RAASI group, this could be due to the finding of higher total vasopressor requirements used in the non-RAASI group to help obtain goal MAP, which could mask any overall between-group differences in MAP. The possibility that the study was underpowered to detect a difference in MAP between groups cannot be ruled out. The results of this study provide support for the conduction of future prospective clinical trials assessing the effects of RAAS inhibition on response to vasopressin infusion in septic shock patients.
CONCLUSION Vasopressin infusion was not associated with a significantly greater increase in 6-hour MAP in septic shock patients who were on chronic RAASI therapy versus those who were not on chronic RAASI therapy. Lower total vasopressor requirements were observed in the RAASI group at 24 hours after vasopressin initiation. Therefore, a prospective randomized trial assessing total vasopressor requirements as the primary outcome would provide more insight regarding the effect of vasopressin in patients with septic shock who are on chronic RAASI therapy prior to hospital admission.
ACKNOWLEDGMENTS We acknowledge Peng Li, PhD, Scientist for the Department of Biostatistics, School of Public Health at the University of Alabama at Birmingham, for his help with reviewing the statistical analyses of this study.
REFERENCES
1. Dellinger RP, Levy MM, Rhodes A, et al; Surviving Sepsis Campaign Guidelines Committee including the Pediatric Subgroup: Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med 2013; 41:580–637 2. Russell JA: Vasopressin in septic shock. Crit Care Med 2007; 35(9 Suppl):S609–S615 XXX 2017 • Volume XX • Number XXX
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Online Clinical Investigation 3. Rhodes A, Evans LE, Alhazzani W, et al: Surviving Sepsis Campaign: International guidelines for management of sepsis and septic shock: 2016. Intensive Care Med 2017; 43:304–377 4. Holmes CL, Patel BM, Russell JA, et al: Physiology of vasopressin relevant to management of septic shock. Chest 2001; 120:989–1002 5. Lange M, Van Aken H, Westphal M, et al: Role of vasopressinergic V1 receptor agonists in the treatment of perioperative catecholaminerefractory arterial hypotension. Best Pract Res Clin Anaesthesiol 2008; 22:369–381 6. Barrett KE, Barman SM, Boitano S, et al: Ganong’s Review of Medical Physiology. 23rd Edition. New York, McGraw-Hill Companies, 2010, pp 665–672 7. Landry DW, Levin HR, Gallant EM, et al: Vasopressin deficiency contributes to the vasodilation of septic shock. Circulation 1997; 95:1122–1125
Critical Care Medicine
8. Hasija S, Makhija N, Choudhury M, et al: Prophylactic vasopressin in patients receiving the angiotensin-converting enzyme inhibitor ramipril undergoing coronary artery bypass graft surgery. J Cardiothorac Vasc Anesth 2010; 24:230–238 9. Meersschaert K, Brun L, Gourdin M, et al: Terlipressin-ephedrine versus ephedrine to treat hypotension at the induction of anesthesia in patients chronically treated with angiotensin converting-enzyme inhibitors: A prospective, randomized, double-blinded, crossover study. Anesth Analg 2002; 94:835–840, table of contents 10. Boccara G, Ouattara A, Godet G, et al: Terlipressin versus norepinephrine to correct refractory arterial hypotension after general anesthesia in patients chronically treated with renin-angiotensin system inhibitors. Anesthesiology 2003; 98:1338–1344 11. Russell JA, Walley KR, Singer J, et al; VASST Investigators: Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl J Med 2008; 358:877–887
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7
Objectives: To compare the hemodynamic response in septic shock patients receiving vasopressin who were on chronic reninangiotensin-aldosterone system inhibitor therapy with those who were not. Design: Single-center, retrospective cohort study. Setting: Medical and surgical ICUs at a 1,100-bed academic medical center. Patients: Medical and surgical ICU patients with septic shock who received vasopressin infusion added to at least one concomitant vasopressor agent between January 2014 and December 2015, then divided into two cohorts: 1) patients who were on chronic renin-angiotensin-aldosterone system inhibitor therapy as outpatients and 2) patients who were not on chronic renin-angiotensinaldosterone system inhibitor therapy as outpatients. Interventions: None. Measurements and Main Results: Mean arterial pressure at 6 hours was 72.2 mm Hg in the renin-angiotensin-aldosterone system inhibitor group versus 69.7 mm Hg in the non–renin-angiotensin-aldosterone system inhibitor group (p = 0.298). There was no difference in mean arterial pressure at 1, 24, or 48 hours between groups. Total concomitant vasopressor requirements, based on norepinephrine equivalents excluding vasopressin, were significantly lower at 24
Department of Pharmacy, University of Alabama at Birmingham Hospital, Birmingham, AL. 2 Department of Anesthesiology, University of Alabama at Birmingham, Birmingham, AL. 3 Division of Acute Care Surgery, Department of Surgery, University of Alabama at Birmingham Hospital, Birmingham, AL. 4 Department of Biostatistics, University of Alabama at Birmingham, Birmingham, AL. This research was performed at University of Alabama at Birmingham Hospital, Birmingham, AL. The authors have disclosed that they do not have any potential conflicts of interest. Address requests for reprints to: Beth L. Erwin, PharmD, BCCCP, University of Alabama at Birmingham Hospital, JT 1728, 619 19th Street South, Birmingham, AL 35249. E-mail: [email protected] Copyright © 2017 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved. DOI: 10.1097/CCM.0000000000002729 1
Critical Care Medicine
hours in the renin-angiotensin-aldosterone system inhibitor group versus the non–renin-angiotensin-aldosterone system inhibitor group (10.7 vs 18.1 µg/min, respectively; p = 0.007), but no significant differences were seen at the other time points assessed. There were no significant differences in ICU or hospital length of stay or mortality. Conclusions: There was no significant difference in the primary outcome of 6-hour mean arterial pressure in septic shock patients receiving vasopressin who were on chronic renin-angiotensinaldosterone system inhibitor therapy versus those receiving vasopressin who were not on chronic renin-angiotensin-aldosterone system inhibitor therapy. Renin-angiotensin-aldosterone system inhibitor patients had lower total concomitant vasopressor requirements at 24 hours compared with non–renin-angiotensin-aldosterone system inhibitor patients. (Crit Care Med 2017; XX:00–00) Key Words: angiotensin-converting enzyme inhibitors; angiotensin receptor antagonists; hemodynamics; renin-angiotensin system; shock; septic; vasopressins
S
epsis is a state of systemic inflammation that manifests in response to infection. Septic shock, defined as sepsis-induced hypotension refractory to fluid resuscitation (1), is a leading cause of death in the ICU, with documented mortality rates as high as 50–85% (2). Both the 2012 and the 2016 Surviving Sepsis Campaign guidelines recommend norepinephrine as the first-line vasopressor for management of septic shock, with a target mean arterial pressure (MAP) of 65 mm Hg (1, 3). The guidelines support the addition of low-dose vasopressin (at a rate of 0.03 [2016 guidelines] to 0.04 units/min [2012 guidelines]) to norepinephrine in order to reach target MAP or to limit norepinephrine requirements, but they do not favor its use as initial vasopressor therapy in this septic shock population (1, 3). One notable advantage of vasopressin in the management of septic shock is its ability to enhance vascular sensitivity to catecholamines (4). Another potential advantage is its organ-specific vasodilatory effects, which in contrast to catecholamines may provide some degree of pulmonary vasodilation (4). The sympathetic nervous system, renin-angiotensinaldosterone system (RAAS), and vasopressin system are all www.ccmjournal.org
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critical pathways involved in acute blood pressure regulation (5). Among these various mechanisms contributing to hemodynamic stability are hormones with vasoconstrictor properties, two of which are vasopressin and angiotensin II. Vasopressin, also known as “antidiuretic hormone,” is a neurohormone that is released from the posterior pituitary in response to increased plasma osmolality and decreased plasma volume (6). In states of shock, vasopressin acts on vascular V1 receptors to induce vasoconstriction and rapidly restore blood pressure (6). However, it has been noted that vasopressin levels in patients with septic shock are inappropriately low (7). Angiotensin II, a component of the RAAS, regulates plasma volume and MAP via direct arteriolar vasoconstriction and stimulation of aldosterone release to increase sodium reabsorption. In addition to its direct vasoconstrictive properties, angiotensin II acts on the CNS to promote the secretion of vasopressin (6), which is a mechanism of particular importance to the current study. RAAS inhibitors (RAASIs), such as angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), are medications commonly prescribed to treat various chronic diseases including hypertension, congestive heart failure, and ischemic heart disease. Because chronic RAAS inhibition compromises one of the three primary endogenous responses to low arterial pressures, the role of vasopressin as a regulator of vascular tone may be of greater importance in this patient population. Also, given the relative state of vasopressin deficiency that occurs in septic shock, in combination with inhibited angiotensin II-mediated secretion of vasopressin in patients on chronic RAASIs, it seems plausible that patients on chronic RAASI therapy who present with septic shock would have a more profound response to treatment with vasopressin compared with patients not on chronic RAASI therapy. Hasija et al (8) found that low-dose vasopressin was successful in preventing postoperative hypotension in patients undergoing coronary artery bypass graft (CABG) surgery who received the preoperative ACEI , ramipril. In another study, Meersschaert et al (9) concluded that when combined with terlipressin, a synthetic vasopressin analog, ephedrine was more effective at treating anesthesia-induced hypotension than ephedrine alone in patients on chronic ACEI therapy. Similarly, Boccara et al (10) found that the effects of terlipressin were more rapid than norepinephrine for maintaining blood pressure during general anesthesia in patients receiving RAASIs. The majority of published studies involving the use of vasopressin as a regulator of arterial pressure in patients on chronic RAASIs were conducted during the perioperative period in patients undergoing various surgical procedures. The investigators of the current study are not aware of any published literature regarding the effects of chronic RAAS inhibition on the hemodynamic response to vasopressin in the population of patients with septic shock. The investigators of this study hypothesized that patients receiving chronic RAASIs who developed septic shock would have a greater response to vasopressin infusion, as evidenced by increased MAPs and decreased concomitant vasopressor requirements, compared with septic shock patients not receiving chronic RAASI therapy. 2
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MATERIALS AND METHODS This research was approved by the University of Alabama at Birmingham Institutional Review Board. A retrospective chart review of medical and surgical patients with septic shock who received vasopressin infusion between January 1, 2014, and December 31, 2015, was conducted at a single 1,100-plus-bed academic medical center. The primary outcome assessed was MAP at 6 hours (T6) after vasopressin initiation (T0). Secondary outcomes included MAP at 1 hour (T1), 24 hours (T24), and 48 hours (T48) after vasopressin initiation; total concomitant vasopressor requirements at T1, T6, T24, and T48; ICU and hospital length of stay; and ICU and hospital mortality. Concomitant vasopressor doses were converted to norepinephrine equivalents using the following conversion originally adopted in the Vasopressin and Septic Shock Trial (11): norepinephrine (µg/min) = epinephrine (µg/min) = phenylephrine (µg/min)/10 = dopamine (µg/kg/min)/2. Patient Selection All medical and surgical ICU patients who received vasopressin infusion during the specified 2-year timeframe, as identified by the hospital’s electronic database, were assessed for inclusion in the current study. Patients were screened for exclusion criteria in the following order: age less than 19 years, pregnant, initiation of vasopressin greater than 5 days since admission, duration of vasopressin less than 6 hours, vasopressin rate less than 0.02 or greater than 0.04 units/min, initiation of another vasopressor agent within 24 hours after vasopressin initiation, not on another vasopressor for at least 1 hour prior to vasopressin initiation, initiation of a steroidal agent within 6 hours after vasopressin initiation, and indication other than septic shock. The following data were collected for each patient: age; gender; body mass index; medical versus surgical ICU admission; history of diabetes mellitus, hypertension, peripheral artery disease, chronic kidney disease, heart failure, or coronary artery disease; ICU death or discharge; hospital death or discharge; ICU length of stay; hospital length of stay; outpatient RAASI therapy (medication name and dose); vasopressin start time, stop time, and infusion rate; concomitant vasopressor requirements at the time of vasopressin initiation; concomitant use of vasopressors while receiving vasopressin; concomitant use of steroids; MAP at prespecified time points; and baseline Sequential Organ Failure Assessment (SOFA) score, lactate, and pH. History of outpatient RAASI therapy was determined by reviewing history and physical notes, reviewing the patient’s medication history that is documented for all patients upon admission when feasible, and reviewing the patient’s external prescription fill history which contains prescription records provided by community pharmacies and pharmacy benefits managers. Of note, patients who were on outpatient spironolactone, an aldosterone antagonist, were not included in the RAASI group since its effects on vascular tone are likely clinically insignificant. Invasive measurements for MAP were used when available. Vasopressin start time was determined based on the time the nurse scanned the infusion bag which charts XXX 2017 • Volume XX • Number XXX
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Online Clinical Investigation
the initiation time in the electronic medication administration record (MAR). Vasopressin stop time was determined by the time of order discontinuation or the time the infusion was documented at a rate of zero in the electronic MAR, whichever came first.
the time of vasopressin initiation, addition of another vasopressor within the first 24 hours after vasopressin initiation, and duration of vasopressin infusion less than 6 hours. Table 1 displays the patient demographics and baseline characteristics. Thirty-seven patients were receiving outpatient RAASI therapy, Statistical Analysis whereas 63 patients were not. Of the 37 patients on chronic A power analysis was conducted and revealed that 100 patients RAASI therapy, 26 patients were on an ACEI, and 11 patients would be needed to detect a between-group difference in MAP were on an ARB, with lisinopril being the most commonly increase from baseline (time of vasopressin initiation) to 6 used ACEI and losartan being the most commonly used ARB. No patients were receiving the renin inhibitor, aliskiren. No hours of 20%, with 80% power. For all analyses, a p value of patients received a RAASI dose while inpatient prior to startless than 0.05 was considered statistically significant. ing vasopressin therapy. Patients in the RAASI group were more Student’s t test was used for comparison of continuous data likely to be older than those in the non-RAASI group, with an (MAP, total vasopressor requirements, length of stay, etc.). The average age of 68 versus 60 years, respectively (p = 0.006). As Fisher exact test was used for comparison of categorical data expected, RAASI patients tended to have more preexisting con(preexisting conditions, mortality, etc.). For MAP and total concomitant vasopressor requirements, a linear mixed model was ditions, although hypertension was the only one that reached used to assess the effects of RAAS inhibition over time. Unless statistical significance (81% vs 54%; p = 0.006). There were no otherwise specified, data are expressed as mean ± sd. All statis- significant between-group differences in baseline SOFA score, tical analyses were conducted using SAS software, version 9.4 lactate, pH, or total vasopressor requirements at T0. At T0, 89.2% of RAASI patients were receiving norepi(SAS Institute, Cary, NC). nephrine, 13.5% receiving phenylephrine, and 5.4% receiving epinephrine. In the non-RAASI group, 98.4% of patients RESULTS were receiving norepinephrine, 6.3% receiving phenylephSubjects rine, and 4.8% receiving epinephrine at baseline. No patients During the 24-month study period, 596 patients were idenwere receiving dopamine at T0. Ninety-two percent of RAASI tified as having received vasopressin infusion, of which 100 patients and 90% of non-RAASI patients were receiving a sinmet inclusion criteria (Fig. 1). The most common reasons for gle vasopressor at T0, with the remainder of patients in each patient exclusion were hospitalization greater than 5 days at group receiving two vasopressor agents at T0. Baseline vasopressor requirements are listed in Table 1. Sixty-three percent of study patients had all MAPs measured invasively via an arterial catheter. Nineteen percent of patients had only noninvasive MAP measurements. Fourteen percent were changed from noninvasive to invasive MAP measurement within 24 hours from T0, whereas 4% were switched from invasive to noninvasive MAP measurement during this time period. The mean vasopressin duration among RAASI patients was 66.5 hours (median 48 hr) compared with a mean duration of 64.1 hours (median 39 hr) among non-RAASI patients. Ninety-five percent of RAASI patients remained on vasopressin at 24 hours and thus were included in the T24 analyses compared with 90% of patients in the non-RAASI group. Fifty-four percent of Figure 1. Patient selection. ACEI = angiotensin-converting enzyme inhibitor, ARB = angiotensin receptor RAASI patients were able to blocker, RAASI = renin-angiotensin-aldosterone system inhibitor. Critical Care Medicine
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TABLE 1.
Patient Demographics and Baseline Characteristics
Characteristics
RAASI
No RAASI
p
Age (yr), mean (sd)
67.5 (11.4)
59.7 (14.4)
0.006
Male gender, n (%)
24 (64.9)
34 (54)
0.287
28.6 (8.8)
0.873 0.799
Body mass index (kg/m2), mean (sd)
28.9 (5.9)
Location, n (%) Medical ICU
29 (78.4)
51 (81)
Surgical ICU
8 (21.6)
12 (19)
Hypertension
30 (81.1)
34 (54)
0.006
Diabetes
16 (43.2)
19 (30.2)
0.185
Heart failure
10 (27)
9 (14.3)
0.117
Coronary artery disease
10 (27)
13 (20.6)
0.463
Chronic kidney disease
14 (37.8)
14 (22.2)
0.093
1 (2.7)
1 (1.6)
0.701
8.8 (2.8)
8.6 (2.8)
0.759
7.30 (0.1)
7.29 (0.2)
0.748
4.4 (3.3)
4.2 (3.9)
0.862
107 (22)
105 (22)
0.723
70 (10.5)
67.2 (12.3)
0.243
One
34 (91.9)
57 (90.4)
0.999
Two
3 (8.1)
6 (9.5)
Norepinephrine
33 (89.2)
62 (98.4)
0.054
Phenylephrine
5 (13.5)
4 (6.3)
0.394
Epinephrine
2 (5.4)
3 (4.8)
0.214
Preexisting conditions, n (%)
Peripheral artery disease Sequential Organ Failure Assessment score, mean (sd) pH, mean (sd) Lactate (mg/dL), mean (sd) Heart rate (beats/min), mean (sd) Mean arterial pressure at time 0 (mm Hg), mean (sd) Vasopressor(s) utilized at time 0, n (%)
Vasopressor(s) used at time 0, n (%)
Vasopressor requirements at time 0 (µg/min), mean (sd) Norepinephrine
27.6 (12.2)
26.6 (12.4)
0.682
Phenylephrine
180 (125.5)
243.8 (96.6)
0.539
Epinephrine Total concomitant vasopressor requirements at time 0 (µg/min), mean (sd)
11 (1.4)
7.3 (4.6)
0.388
27.7 (14.1)
28.2 (14.3)
0.865
RAASI = renin-angiotensin-aldosterone system inhibitor.
be included in the T48 analyses versus 51% of non-RAASI patients. Steroids were initiated prior to vasopressin therapy in 27% of RAASI patients and in 22% of non-RAASI patients. Outcomes There was no significant difference between groups in the primary outcome of MAP at T6, with an average 6-hour MAP of 72.2 mm Hg in the RAASI group versus 69.7 mm Hg in the non-RAASI group (p = 0.298). No differences were found in the secondary outcomes of MAP at T1, T24, or T48 or total 4
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vasopressor requirements at T1, T6, or T48. However, lower total vasopressor requirements at T24 were observed in the RAASI group compared with the non-RAASI group (10.7 vs 18.1 µg/min, respectively; p = 0.007). There were no betweengroup differences in ICU mortality, hospital mortality, ICU length of stay, or hospital length of stay. Table 2 displays both the primary and secondary outcomes results. The results of the linear mixed model for MAP are displayed in Figure 2, which portrays the estimated average MAP for each group over time. There was a nonsignificant trend for subjects XXX 2017 • Volume XX • Number XXX
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Online Clinical Investigation
TABLE 2.
Primary and Secondary Outcomes RAASI, Mean (sd)
No RAASI, Mean (sd)
p
MAP at 1 hr (mm Hg)
74.7 (10.5)
71.4 (10.2)
0.128
MAP at 6 hr (mm Hg)
72.2 (10.9)
69.7 (11.8)
0.298
MAP at 24 hr (mm Hg)
75.4 (8.7)
71.4 (12.3)
0.095
MAP at 48 hr (mm Hg)
73.4 (8.9)
72 (11.4)
0.655
Concomitant vasopressor requirements at 1 hr (µg/min)
25.3 (14.9)
25.8 (13.5)
0.841
Concomitant vasopressor requirements at 6 hr (µg/min)
21.8 (13.7)
23.5 (13.6)
0.563
Concomitant vasopressor requirements at 24 hr (µg/min)
10.7 (10.9)
18.1 (13.4)
0.007
Concomitant vasopressor requirements at 48 hr (µg/min)
9.4 (14)
13 (13.7)
0.356
ICU
10.6 (9.9)
11.8 (12.7)
0.631
Hospital
19.3 (18.2)
16.1 (14.4)
0.341
ICU
45.9
55.6
0.353
Hospital
48.6
65.1
0.107
Outcomes
a
Length of stay (d)
Mortality (%)
MAP = mean arterial pressure, RAASI = renin-angiotensin-aldosterone system inhibitor. a Primary outcome.
receiving RAASIs to have higher MAPs (p = 0.072) during this time period. The interaction between RAAS inhibition and time was not significant (p = 0.931). Figure 3 displays total vasopressor requirements over 48 hours, which decreased over time for both groups. RAASI patients had significantly lower total vasopressor requirements (p = 0.003). The interaction between RAAS inhibition and time trended toward significance (p = 0.056), indicating that patients on chronic RAASI therapy may have had a faster decrease in total vasopressor requirements compared with patients not on chronic RAASI therapy.
DISCUSSION
Figure 2. Mean arterial pressure from T0 to T48. RAASI = reninangiotensin-aldosterone system inhibitor.
Figure 3. Total concomitant vasopressor requirements from T0 to T48. RAASI = renin-angiotensin-aldosterone system inhibitor.
Critical Care Medicine
The study by Hasija et al (8) of prophylactic vasopressin in patients receiving preoperative ramipril undergoing CABG surgery found that of the patients who continued ramipril until the morning of surgery, those who received prophylactic vasopressin had higher MAPs after the termination of cardiopulmonary bypass and also had lower total vasopressor requirements than those who did not receive vasopressin. Although the current study did find similar results in regard to reduced total vasopressor requirements at 24 hours after
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vasopressin initiation in the RAASI group, it is difficult to directly compare the two studies given the different patient populations studied, as well as the impact of anesthesia on MAP and vasopressin response in the study by Hasija et al (8). Similarly, Meersschaert et al (9) conducted a randomized, crossover, double-blind study comparing terlipressin plus ephedrine versus ephedrine alone in the treatment of anesthesia-induced hypotension and found that patients with a partially blocked endogenous response to hypotension, such as those on an ACEI, had fewer second hypotensive episodes, a shorter duration of hypotension, and lower median doses of ephedrine. Again, the effects of anesthesia on the sympathetic nervous system’s ability to contribute to MAP regulation would confound any true comparison of these results to the current study. The study by Boccara et al (10) was also conducted in the operative arena where anesthesia was used. The results of the current study focus on the response to vasopressin infusion in patients on chronic RAASIs outside of the operative arena, specifically in patients with septic shock. The current study has limitations. Given the retrospective design of the study, determination of outpatient RAASI therapy relied upon documentation in the electronic medical record (EMR). Neither adherence to outpatient therapy nor time of last RAASI dose was able to be confirmed. In addition, EMR documentation was used to determine vasopressor start times and infusion rates, as nurses were allowed to titrate vasopressors (other than vasopressin) to obtain target MAP based on physician-defined variables. MAP at T6 was chosen as the primary endpoint with concomitant vasopressor requirements as a secondary endpoint; however, future studies may consider assessing concomitant vasopressor requirements as the primary endpoint given that nursing documentation of MAP may succeed a titration in concomitant vasopressor doses. The study was not powered to detect a difference in the clinical endpoints of length of stay and mortality. It is worth noting that source of infection, culture data, antibiotic therapy, fluid administration, vasopressin serum levels, and adverse effects were not assessed. It is possible that physician preference led to the initial addition of vasopressin to a select group of patients with septic shock given the nonrandomized nature of the study. However, excluding patients for whom vasopressin was chosen as the first-line vasopressor minimized this type of bias and allowed for evaluation of only those patients who were managed hemodynamically in accordance with the 2012 Surviving Sepsis Campaign guidelines. Because this study included only medical and surgical ICU patients with septic shock, these results cannot be generalized to other patient populations. The higher percentage of patients with hypertension, diabetes, heart failure, and chronic kidney disease in the RAASI group is expected given the indications for RAASIs. These differences are unlikely to have impacted the outcome given the similar baseline SOFA scores between groups. Also, one cannot rule out the possibility that patients who are on chronic RAASI therapy have a common underlying pathophysiologic process that led to the decreased vasopressor requirements at 24 hours after 6
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vasopressin initiation, with the outpatient initiation of RAASI therapy serving only as a surrogate marker for this underlying process. Because this study was nonrandomized with a relatively small sample size, the nonsignificant p values in baseline characteristics do not ensure similarity between groups. One major strength of the current study is the inclusion of patients who were on RAASI therapy for any indication, which allows for generalizability of the results to patients with a variety of disease states including hypertension, heart failure, and chronic kidney disease. Second, the study is strengthened by its focus on patients with septic shock since other types of shock are not associated with the same level of endogenous vasopressin depletion, and thus the addition of vasopressin might not play as big of a role in patients on chronic RAASIs. And third, this study found several trends in secondary endpoints that might have proven significant with adequate power, such as a trend toward reduced vasopressor requirements over time and a trend toward lower overall mortality in RAASI patients. Although 6-hour MAP was not found to be statistically significantly higher in the RAASI group, this could be due to the finding of higher total vasopressor requirements used in the non-RAASI group to help obtain goal MAP, which could mask any overall between-group differences in MAP. The possibility that the study was underpowered to detect a difference in MAP between groups cannot be ruled out. The results of this study provide support for the conduction of future prospective clinical trials assessing the effects of RAAS inhibition on response to vasopressin infusion in septic shock patients.
CONCLUSION Vasopressin infusion was not associated with a significantly greater increase in 6-hour MAP in septic shock patients who were on chronic RAASI therapy versus those who were not on chronic RAASI therapy. Lower total vasopressor requirements were observed in the RAASI group at 24 hours after vasopressin initiation. Therefore, a prospective randomized trial assessing total vasopressor requirements as the primary outcome would provide more insight regarding the effect of vasopressin in patients with septic shock who are on chronic RAASI therapy prior to hospital admission.
ACKNOWLEDGMENTS We acknowledge Peng Li, PhD, Scientist for the Department of Biostatistics, School of Public Health at the University of Alabama at Birmingham, for his help with reviewing the statistical analyses of this study.
REFERENCES
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Critical Care Medicine
8. Hasija S, Makhija N, Choudhury M, et al: Prophylactic vasopressin in patients receiving the angiotensin-converting enzyme inhibitor ramipril undergoing coronary artery bypass graft surgery. J Cardiothorac Vasc Anesth 2010; 24:230–238 9. Meersschaert K, Brun L, Gourdin M, et al: Terlipressin-ephedrine versus ephedrine to treat hypotension at the induction of anesthesia in patients chronically treated with angiotensin converting-enzyme inhibitors: A prospective, randomized, double-blinded, crossover study. Anesth Analg 2002; 94:835–840, table of contents 10. Boccara G, Ouattara A, Godet G, et al: Terlipressin versus norepinephrine to correct refractory arterial hypotension after general anesthesia in patients chronically treated with renin-angiotensin system inhibitors. Anesthesiology 2003; 98:1338–1344 11. Russell JA, Walley KR, Singer J, et al; VASST Investigators: Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl J Med 2008; 358:877–887
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