Shock is a state of severe systemic deterioration in tissue perfusion, characterized by decreased cellular oxygen delivery and utilization as well as decreased removal of waste by-products of metabolism (1). The current definition for septic shock in adults describes a state of acute circulatory failure characterized by persistent hypotension despite adequate fluid resuscitation due to an infectious source (probable or documented) (2). Sepsis-induced hypotension is further defined as a systolic blood pressure of less than 90 mmHg, mean arterial pressure of less than 70 mmHg, or a reduction in systolic blood pressure of greater than 40 mmHg or less than 2 SDs below normal for age in the absence of other causes of hypotension (2, 3). Implementation of early goal-directed therapy in patients with septic shock has significantly decreased mortality rates (4); however, sepsis still remains a leading cause of morbidity and mortality in critically ill patients (5). Mortality rates from septic shock vary and have been quoted as high as 61% in some patient populations, demonstrating the devastating and complex nature of the disease process (6–9). Previous studies have also shown mortality from sepsis is highest among African American (AA) males (7). Although many facets of the management of septic shock have been explored, to the authors’ knowledge no previous studies have analyzed differences in vasopressor requirements among various ethnic groups.
Differences in the physiology of blood pressure regulation between AAs and white patients have been well described dating back to 1932 (10). Blood pressure regulation in the human body is multidimensional with remarkable heterogeneity from a clinical and biochemical standpoint (11). Multiple factors have been shown to affect blood pressure control between races including psychological and socioeconomic factors (12), sodium sensitivity, insulin resistance, cation transport, microvascular injury, renal physiology, and adrenergic activity (11, 12).
Although there is a large body of literature describing variations in blood pressure regulation and treatment response for hypertension (HTN) between various ethnic groups, the association between the race and vasopressor requirements in critically ill patients with septic shock has not previously been described. Just as blood pressure regulation and treatment differ among races when describing HTN, we hypothesize that blood pressure regulation and vasopressor requirements for patients experiencing hypotension during septic shock will vary between AAs and whites.
MATERIALS AND METHODS
The study was conducted at an 805-bed, tertiary, academic teaching institution over a 2-year period. The study cohort consisted of all patients admitted to the intensive care unit (ICU) requiring the initiation of vasopressor therapy for the management of septic shock identified by our institutional sepsis registry. All patients enrolled met the definition of septic shock described by Dellinger et al. (2). Exclusion criteria for this study included any patient younger than 18 years, any patient not identified by the institutional sepsis registry as AAs or white patients, and any patient who had initiation of vasopressors outside the ICU setting. Patients diagnosed with septic shock outside our ICU setting and started on vasopressors at that time were excluded from the study to allow for better uniformity of treatment decisions. This was done to control for treatment decisions by reviewing only those septic shock patients managed by critical care physicians in the ICU. Septic shock management was identical for all patients for the first 6 h in accordance with early goal-directed therapy established by Rivers et al. (4). After the initial resuscitative period, management was at the discretion of the treating critical care physician and in accordance with Surviving Sepsis Campaign guidelines (2). Vasopressor selection was based on the judgment of the treating physician following Surviving Sepsis Campaign guidelines (2).
An institutional review board approved the retrospective review of our institutional sepsis database and electronic medical record data review for the length of ICU stay. Consent for involvement in the study was waived because of the retrospective nature of the review. Baseline demographics included age, sex, mortality, comorbidities, prehospital antihypertensive medications, source of infection, total intravenous (IV) fluids, and hemodynamic parameters. Sequential Organ Failure Assessment (SOFA) scores and Acute Physiology and Chronic Health Evaluation (APACHE) II scores were calculated for each patient. Antihypertensive medications were categorized into β-blockers, calcium-channel blockers, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, diuretics, and others.
The different vasopressors utilized in the study include norepinephrine (NE), phenylephrine (Phe), dopamine (Dop), and epinephrine (Epi). Vasopressin was not analyzed as a vasopressor in this study because of its different mechanism of action and also because it is often used in conjunction with these other vasopressors during septic shock for its synergistic effects. Total vasopressor dosage and duration of use were obtained. Mean hourly dosage was then calculated as the total dose used over the total duration of the vasopressor given. The number of vasopressors required by each patient was also reviewed. Univariate analysis with χ2 test, Fisher exact, Wilcoxon signed rank test, and t test was conducted. A multivariate analysis was then conducted using a stepwise logistic regression model (SAS 9.2; SAS Institute Inc., Cary, NC) to identify any statistically significant associations. Statistical analysis with P < 0.05 was considered statistically significant.
The study included 159 septic shock patients; 81 (51%) were female, and 96 (60%) were AAs. The mean age of the AA group was 63.7 (15.9) years, and that of the white groups was 60.1 (16.5) years (P < 0.991). Summary of the baseline demographics can be found in Table 1. There was no significant difference in APACHE II score, SOFA score, or overall hospital mortality between the two groups. African Americans did have significantly higher rates of end-stage renal disease and HTN compared with whites, 85.7% vs. 14.3% (P < 0.011) and 68.3% vs. 31.7% (P < 0.007), respectively. There was no statistically significant difference in hemodynamic profile, sepsis volume resuscitation goals, inotrope support, or steroid use (Table 1). Of the combined septic shock groups, 100 patients (63%) required only one vasopressor, 36 (23%) required two vasopressors, and 23 (15%) required three or more vasopressors with no statistical difference between AAs and white patients (Table 1).
Table 2 lists the various sources of infection found in the two groups. The AA group had a significantly higher incidence of bloodstream infections, 8.2% vs. 0.6% (P < 0.017), and other infectious sources 11.3% vs. 2.5% (P < 0.015). Other infectious sources include skin and soft tissue, bone, and so on. White patients had a higher incidence of abdominal infectious source compared with the AA group, 13.8% vs. 10.7% (P < 0.008).
The total and mean dosages of NE for management of septic shock in AAs were found to be statistically significant as was the total duration of NE administered to AAs compared with whites. The total dose of NE was 736.8 (897.3) μg compared with 370.6 (554.2) μg for white patients (P < 0.003). The total duration of NE administered was 38.38 (34.75) h for AAs versus 29.09 (27.11) h for whites (P < 0.037), and the mean dose of NE was AAs 21.08 (22.23) μg/h vs. whites 12.37 (13.86) μg/h (P < 0.01). There was no statistical significance between the AA and white cohorts for the individual vasopressor starting or maximum dosages. Table 3 is a summary of the starting, maximum, total, and mean dosages of vasopressors administered as well as vasopressor administration duration between ethnicities. Table 4 lists the logistic regression model for the AA race using the mean dose variables for each of the vasopressors with significance associated for the NE mean dose (odds ratio, 1.043; confidence interval, 1.010–1.078).
As previously stated, the incidence of HTN was significantly different between the AA and white groups (P < 0.007) (Table 1). There was no statistical difference in the distribution of antihypertensive medications between the AA and white groups. An analysis of each of the five antihypertensive medication categories compared with the mean dose of NE is shown in Table 5, with no statistical significance found between those taking and not taking antihypertensive medications.
The exact mechanism through which blood pressure is regulated remains unclear because of the multifocal nature of its physiology. It is, however, very apparent from current literature that race plays a role in blood pressure regulation, at least for those individuals who develop HTN (11–13). Our study observed blood pressure regulation and response through the lens of critical illness, describing how patients of different ethnic backgrounds responded to vasopressor support during the hypotensive septic shock state. To our knowledge, this question had not been previously explored.
In our study, we observed that the AA cohort required significantly higher amounts of NE to obtain a MAP of 65 mmHg or greater during septic shock when compared with the white patient cohort. Furthermore, the AA cohort also required a longer duration of NE administration to maintain a MAP of 65 mmHg or greater that was found to be statistically significant. This was evident even with similar IV fluid resuscitation, steroid requirements, and vasopressin administration between the two groups. Even though not statistically significant, AAs also required higher amounts of Phe and Epi compared with whites. The number or type of blood pressure medications a hypertensive patient was taking before the development of septic shock had no significant effect on the overall vasopressor requirements. Furthermore, our study revealed that AAs who developed septic shock had higher incidences of HTN and end-stage renal disease before the development of septic shock. Finally, our study demonstrated that the AA cohort developed septic shock more frequently from bloodstream infections or other infectious sources, whereas the white cohort was more likely to develop septic shock from abdominal infections.
Two earlier studies by Dimsdale and Sherwood examined the blood pressure response to vasopressors between AAs and whites; however, the patients receiving vasopressors in these studies were normotensive and not in a state of septic shock (14, 15). Dimsdale et al. (14) infused NE into normotensive patients, demonstrating an increased sensitivity to the vasopressor from AAs, but only after salt-loading these patients with 200 mEq of salt per day. Sherwood and Hinderliter (15) demonstrated that AA men had a higher sensitivity to Phe infusion than that of white men. Our patient population, however, was studied while in a state of hypotension secondary to septic shock, which was quite different than these previous studies. Whether our results are a consequence of the physiologic stress and multifactoral nature of septic shock altering adrenergic receptor response is yet to be studied.
Many studies have examined differences between AAs and whites in terms of the development of HTN. African Americans have been shown to have a suppressed angiotension-renin system compared with salt intake and secretion (11, 12, 16). African Americans have also been shown to express lower levels of Dop-β-hydroxylase (the enzyme that converts Dop to Epi) (17), resulting in lower levels of endogenous Epi (18). Blood pressure maintenance in AAs has been shown to be more regulated by nonadrenergic mechanisms compared with whites (19, 20). Furthermore, there are at least seven different adrenergic receptor genetic polymorphisms (21) and significant adrenergic receptor density differences and sensitivities between AAs and whites (18, 22–24). Although we cannot extrapolate HTN research to that of the hypotensive septic shock patient, examination of these previously conducted studies about blood pressure regulation differences between ethnicities does raises many interesting questions. Whether our results are due to the physiologic stress, end-organ failure, and the multifactoral nature of septic shock, differences in adrenergic receptor sensitivity and density or genetics cannot be determined from this study and will need further investigation.
There are multiple limitations to our study. First, it was a retrospective review from a single center. Our study compared vasopressor requirements for patients managed by a variety of critical care physicians with different management strategies. A larger, prospective multi-institutional, multicontinental double-blind study with a vasopressor management protocol is needed to better validate our results. Second, the majority of our patients reviewed received NE as the vasopressor of choice, most likely due to the efficacy of this medication demonstrated in the literature (2, 25, 26). A larger study with a greater number of patients receiving the other vasopressors utilized needs to be completed as our trends indicated the AA cohort would require statistically higher dosages of these vasopressors as well. Of note, the average starting dose of Epi in our study was higher for AAs than the average maximum dose. This is most likely due to the small sample size of patients receiving Epi with extreme outliers. With a larger sample size, we anticipate this would reverse. Third, our study included a very specific population of septic shock patients, only those patients who were started on vasopressors in the ICU at our institution. Many patients with septic shock are administered vasopressors in the emergency department or at transferring hospitals. Additional studies are needed to examine this patient population and the effects on vasopressor dosing and duration. Finally, our study was limited through the examination of vasopressors requirements in only two racial groups. Further studies should expand the focus of vasopressors requirements to a variety of races including the disparities relating to the use of antihypertensive medications, social background, and additional health conditions other than those we have compared in this study.
Current Surviving Sepsis Campaign guidelines recommend NE as the first-line vasopressor for treatment of septic shock (2), although there are currently no recommendations on the starting dose of this medication. Furthermore, there are currently no guidelines addressing NE dosing disparities among various races. Although NE has been shown to be more efficacious than other vasopressors for the treatment of septic shock through decreased arrhythmias (2, 25), increased mean systemic pressure, and increased venous return to the heart resulting in increased cardiac output (26), future studies may demonstrate various ethnic patient populations require different doses to obtain these positive effects.
Through our study, we have laid the initial groundwork for further studies examining the relationship between vasopressors and race during septic shock as many new questions now arise from our results. We observed that AAs required higher doses and longer duration of vasopressor support, specifically NE, to obtain and maintain a goal MAP of 65 mmHg or greater during septic shock compared with white patients. This was the case irrespective of APACHE II or SOFA scores, IV fluids administered, steroids or vasopressin given, or preshock antihypertensive medications taken. Although we can only speculate as to the reason for these differences in vasopressor requirements among races, it makes sense there would be a difference because multiple studies have demonstrated differences in blood pressure regulation between AAs and whites relative to the development of HTN. Future studies may allow for medical management strategy changes for the septic shock patient, especially between races, allowing for better patient care and overall outcomes. Our group is currently working on a prospective trial to better evaluate these discrepancies.
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Keywords:© 2014 by the Shock Society
Vasopressors; race; septic shock; norepinephrine; hypotension; African American