Arterial Pressure Response to an Increase in Norepinephrine Varies Depending on the Baseline Norepinephrine Dose in Patients With Septic Shock

Septic shock is characterized by the need for vasopressors—typically starting with norepinephrine—to maintain BP. In animal models of shock,1Pang C.C.Y. Tabrizchi R. The effects of noradrenaline, B-HT 920, methoxamine, angiotensin II and vasopressin on mean circulatory filling pressure in conscious rats.Br J Pharmacol. 1986; 89: 389-394Crossref PubMed Scopus (60) Google Scholar,2Peng Z.-Y. Critchley L.A.H. Fok B.S.P. The effects of increasing doses of noradrenaline on systemic and renal circulations in acute bacteraemic dogs.Intensive Care Med. 2005; 31: 1558-1563Crossref PubMed Scopus (17) Google Scholar serial increases in norepinephrine lead to linear mean arterial pressure (MAP) increases up to a dose of 1.35 μg/kg/min. However, preclinical dose-response experiments do not necessarily reflect clinical experience, and little evidence guides clinicians seeking to avoid increases in norepinephrine that yield minimal MAP responses. Despite ubiquitous use of norepinephrine during septic shock, norepinephrine-to-MAP dose-response relationships are uncharacterized in critically ill patients. In this study, we sought to determine the risk-adjusted change in MAP response across norepinephrine doses in patients with septic shock. We used Medical Information Mart for Intensive Care-IV,3Johnson A. Bulgarelli L. Pollard T. Horng S. Celi L.A. Mark R. MIMIC-IV.Physionet. 2020; (Accessed March 8, 2021. https://physionet.org/content/mimiciv/0.4/)Google Scholar a de-identified single-center database (2008-2019) of patients admitted to ICUs at Beth Israel Deaconess Medical Center (Boston, MA). Included patients were adults with a diagnosis of sepsis4Singer M. Deutschman C.S. Seymour C.W. et al.The Third International Consensus definitions for sepsis and septic shock (sepsis-3).JAMA. 2016; 315: 801-810Crossref PubMed Scopus (14586) Google Scholar who were started on norepinephrine alone at a dose between 0.01 (first percentile) and 0.5 (99th percentile) μg/kg/min (ICUs in Medical Information Mart for Intensive Care-IV used weight-based dosing). We identified the first episode when norepinephrine alone was increased by at least 0.005 μg/kg/min, the starting norepinephrine dose before the dose increase (exposure of interest), and the norepinephrine dose change (new norepinephrine dose minus prior norepinephrine dose). We then identified all MAPs (recorded at least hourly as part of routine vital sign collection) in the 120 min before and after each norepinephrine dose increase. We excluded MAPs that occurred after future norepinephrine dose adjustments or after initiation of other vasopressors. Using these MAP values, we defined MAP change (outcome) as the maximum MAP after norepinephrine dose increase minus the minimum MAP before dose increase. Using analysis of covariance,5Clifton L. Clifton D.A. The correlation between baseline score and post-intervention score, and its implications for statistical analysis.Trials. 2019; 20: 43Crossref PubMed Scopus (62) Google Scholar we constructed linear models for MAP change, including terms for the starting norepinephrine dose, norepinephrine dose change, and covariables of age, sex, race/ethnicity, corticosteroid use, minimum MAP before dose increase, Charlson Comorbidity Index,6Charlson M.E. Pompei P. Ales K.L. MacKenzie C.R. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation.J Chronic Dis. 1987; 40: 373-383Abstract Full Text PDF PubMed Scopus (37093) Google Scholar the body fluid culture site used to identify sepsis using Sepsis-3 criteria,4Singer M. Deutschman C.S. Seymour C.W. et al.The Third International Consensus definitions for sepsis and septic shock (sepsis-3).JAMA. 2016; 315: 801-810Crossref PubMed Scopus (14586) Google Scholar and the most recent value before dose increase for positive end-expiratory pressure, heart rate, blood pH, and Sequential Organ Failure Assessment score. Continuous variables were modeled using restricted cubic splines.7Harrell F.E. Regression Modeling Strategies: With Applications to Linear Models, Logistic and Ordinal Regression, and Survival Analysis. Springer International Publishing, Cham2015Crossref Google Scholar From the models, we calculated the marginal mean MAP change across starting norepinephrine doses while holding variables at their sample means. In a sensitivity analysis, we substituted absolute dose change with relative dose change (dose change divided by starting dose) to assess the robustness of results to alternative dose escalation strategies. Norepinephrine doses were reported using norepinephrine base units. R (version 4.2.1) was used for analyses. Among 34,789 adult patients with sepsis, we identified 5,569 patients started on norepinephrine alone, of whom 2,903 had a norepinephrine dose increase. The mean minimum MAP prior to dose increase was 63 (SD, 11) mm Hg, and mean maximum MAP afterward was 72 (SD, 12) mm Hg. The mean Sequential Organ Failure Assessment score was 7 (SD, 3). Additional characteristics of included patients are shown in Table 1. Nadir MAP measurements occurred approximately 15 min before norepinephrine dose increases and returned to pre-dose-increase baselines after approximately 60 min (Fig 1A).Table 1Characteristics of Patients With Septic Shock Who Had Norepinephrine IncreasedCharacteristics at the Time of First Norepinephrine IncreasePatients (n = 2,903)Age in y, mean (SD)67 (15)Male sex1,622 (55.9)Race/ethnicityaRace/ethnicity categories are extracted from the Medical Information Mart for Intensive Care-IV dataset. American Indian/Alaska Native9 (0.3) Asian78 (2.7) Black/African American311 (10.7) Hispanic/Latino84 (2.9) Other119 (4.1) Unable to obtain25 (0.9) Unknown364 (12.5) White1,913 (65.9)Patient weight in kg, mean (SD)83 (28)First culture site associated with Sepsis-3 criteria4Singer M. Deutschman C.S. Seymour C.W. et al.The Third International Consensus definitions for sepsis and septic shock (sepsis-3).JAMA. 2016; 315: 801-810Crossref PubMed Scopus (14586) Google Scholar Blood1,945 (67.0) Respiratory tract444 (15.3) Genitourinary tract405 (14.0) Other109 (3.8)SOFA score, mean (SD)7 (3)Charlson comorbidity index6Charlson M.E. Pompei P. Ales K.L. MacKenzie C.R. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation.J Chronic Dis. 1987; 40: 373-383Abstract Full Text PDF PubMed Scopus (37093) Google Scholar, mean (SD)6 (4)Minimum MAP in mm Hg, mean (SD)63 (11)Heart rate in beats per minute, mean (SD)85 (22)Positive end expiratory pressure, cm H20, mean (SD)4 (4)Blood pH, mean (SD)7.37 (0.11)Corticosteroid use144 (5.0)Data are presented as No. (%) unless otherwise indicated. MAP = mean arterial pressure; SOFA = sequential organ failure assessment score.a Race/ethnicity categories are extracted from the Medical Information Mart for Intensive Care-IV dataset. Open table in a new tab Data are presented as No. (%) unless otherwise indicated. MAP = mean arterial pressure; SOFA = sequential organ failure assessment score. The mean starting norepinephrine dose was 0.08 (SD, 0.07) μg/kg/min, and the mean norepinephrine dose change was 0.04 (SD, 0.05) μg/kg/min. In the linear model, the predicted mean MAP change from a 0.04 μg/min/kg dose change was 8.7 mm Hg (95% CI, 6.7, 10.7) at a starting norepinephrine dose of 0.1 μg/kg/min; 8.5 (95% CI, 6.3, 10.7) at 0.2 μg/kg/min; 7.1 (95% CI, 4.4, 9.7) mm Hg at 0.3 μg/kg/min, 3.5 (95% CI, −1.4, 8.5) at 0.4 μg/kg/min, and −0.5 (95% CI, −9.7, 8.7) at 0.49 μg/kg/min (Fig 1B). Substituting in the relative change in norepinephrine dose yielded similar results: the model continued to show an inflection point at starting norepinephrine doses of approximately 0.2 μg/kg/min, above which MAP responses were smaller (Fig 1C). Using time-varying electronic medical record data, we show evidence for a smaller increase in MAP in response to a norepinephrine increase for patients with septic shock receiving norepinephrine doses above 0.2 μg/kg/min. This potential threshold for a change in norepinephrine effectiveness helps to inform septic shock clinical practice and marks a rational target for future studies of adjunctive vasoactive treatments for septic shock. Our results should be considered in the context of prior work. We previously developed and validated a novel measure of septic shock severity, the ratio of MAP to norepinephrine equivalent dose (MAP/NEQ) that showed a nonlinear relationship with mortality: MAP/NEQ values below approximately 300 mm Hg/μg/kg/min were associated with large increases in mortality.8Bosch N.A. Teja B. Wunsch H. Walkey A.J. Characterization and validation of a novel measure of septic shock severity.Intensive Care Med. 2020; 46: 135-137Crossref PubMed Scopus (10) Google Scholar In the current study, we found that MAP responses were attenuated above starting norepinephrine doses of 0.2 μg/kg/min, which for an MAP of 65 mm Hg translates approximately to the MAP/NEQ of 300 mm Hg/μg/kg/min, at which mortality rises. Thus, MAP/NEQ > 300 mm Hg/μg/kg/min or > 0.2 μg/kg/min of norepinephrine may represent a threshold of norepinephrine-refractory vasoplegia at which noncatecholaminergic adjunct therapies (eg, corticosteroids, vasopressin, angiotensin II) might be considered. In addition, in a 70-kg person, a dose of 0.2 μg/kg/min equates to 14 μg/min, which was the upper dose limit of the “lower-severity” subgroup in the Vasopressin versus Norepinephrine Infusion in Patients with Septic Shock (VASST) trial that suggested lower mortality among patients randomized to vasopressin rather than continued norepinephrine alone.9Russell J.A. Walley K.R. Singer J. et al.Vasopressin versus norepinephrine infusion in patients with septic shock.N Engl J Med. 2008; 358: 877-887Crossref PubMed Scopus (1308) Google Scholar Future studies should examine the effectiveness of treatment strategies initiating adjuncts when norepinephrine dose exceeds 0.2 μg/kg/min vs continuing norepinephrine alone. Our results inform vasopressor practices during the management of septic shock. Clinicians can now anticipate that patients with norepinephrine doses above the approximately 0.2-μg/kg/min threshold are likely to have diminishing MAP responses to increases in norepinephrine. Equipped with the results from our study, a clinician might alter their approach to vasopressor management in hypotensive patients receiving norepinephrine doses > 0.2 μg/kg/min who still require additional treatment to reach MAP goals, such as (1) starting a catecholamine-sparing vasopressor (ie, vasopressin), (2) increasing norepinephrine by a greater amount at doses >0.2 μg/kg/min than at <0.2 μg/kg/min to more efficiently reach MAP goals, or (3) adding adjunctive corticosteroids. Our study has limitations. The range of norepinephrine doses at which no other vasopressors were given was relatively narrow and well below previously published “high-dose” (eg, 1 μg/kg/min) norepinephrine.10Martin C. Medam S. Antonini F. et al.Norepinephrine: not too much, too long.Shock. 2015; 44: 305-309Crossref PubMed Scopus (84) Google Scholar Thus, MAP responses when the norepinephrine dose is above 0.5 μg/kg/min remain unclear. In addition, norepinephrine increases appeared to occur after MAPs already started to increase (Fig 1), suggesting that norepinephrine documentation may lag behind true initiation time. Although we attempted to decrease misspecification of MAP values by using the minimum MAP before each dose increase, possibly some minimum MAP values occurred after the true time of dose increase. However, this potential documentation lag is unlikely to be differential by norepinephrine starting dose and thus would be unlikely to alter the main findings. Last, although we adjusted for granular electronic medical record-based variables that were expected to confound the relationship between norepinephrine dose and BP response, the observational nature of the study increases the risk of unmeasured confounding. Using a granular electronic health record database, we examined associations between norepinephrine dose before a dose increase and MAP response. We found that, on average, doses above 0.2 μg/kg/min were associated with attenuated MAP responses. These results help to inform vasopressor practices and may identify a rational norepinephrine starting dose for future studies of secondary vasopressor and corticosteroid initiation during septic shock.