There was no difference in mechanical ventilation, corticosteroid use, lactate, MAP, or total number of catecholamine agents patients were receiving (Table 1). There was a statistically significant difference in fluids before vasopressin initiation (P = 0.0001), vasopressin dose (P = 0.0001), and catecholamine dose (P = 0.0001) between BMI groups when evaluating fluid volumes and vasopressin and catecholamine doses based on weight.
For the primary objective evaluating the correlation of vasopressin dose adjusted for both weight and BMI (Table 2) and its impact on catecholamine-dose change and MAP change, we found no correlation at 2, 6, or 12 h postvasopressin initiation.
Secondary endpoints evaluated are listed in Table 3; there were no statistically significant differences noted. The median duration of catecholamine use was 2.70 days and was similar among patients when stratified by BMI (P = 0.97). The minority of patients achieved hemodynamic stability (45.4%) and the proportion did not differ by BMI stratification (P = 0.95). Overall, in-hospital mortality was 64.8% and ICU mortality was 59.8% and both remained high among all BMI groups with no statistically significant differences noted.
A total of 938 patients were included in this analysis and no correlation was found between catecholamine-dose change and MAP change at 2, 6, and 12 h after vasopressin initiation when adjusting vasopressin dose for both weight and BMI. Despite many differences in baseline characteristics between the BMI groups, there were no differences in any secondary outcomes including achievement of hemodynamic stability, ICU and in-hospital mortality, ICU- and hospital-free days, and duration of mechanical ventilation and vasopressor support.
The optimal agent, timing of initiation, titration scheme, and hemodynamic goals of vasoactive medications in patients with septic shock are unknown. The SSC Guidelines recommend norepinephrine as the first-line vasopressor and suggest adding vasopressin as an adjunct (5). Vasopressin is currently not recommended as monotherapy for septic shock. In the Vasopressin and Septic Shock Trial (VASST) (6) and the Vasopressin versus Norepinephrine as Initial Therapy in Septic Shock (VANISH) trial (17), two of the largest studies evaluating vasopressin in patients with septic shock, vasopressin was not associated with improvement in mortality compared wih norepinephrine alone or when used in combination with norepinephrine. In a subgroup analysis of patients in VASST with less severe sepsis, defined as norepinephrine dose equivalents less than 15 mcg/min, patients randomized to receive vasopressin had lower 28- and 90-day mortality (6). Patients randomized to receive vasopressin in the VANISH trial less frequently received renal replacement therapy, but this did not result in a mortality difference (17).
Despite a potential mortality benefit and decreased need for renal replacement therapy, neither VASST nor VANISH adequately identified patient characteristics that may be associated with better response to vasopressin. Moreover, vasopressin in both the VASST and VANISH trial was permitted to be titrated and neither study evaluated the impact of body weight nor BMI on outcomes associated with vasopressin therapy (6, 17). Independent investigators later evaluated the mortality rate in VASST by stratifying patients by BMI and found that patients with a BMI less than 25 kg/m2 had the highest mortality rate. Obese and overweight patients received less norepinephrine, vasopressin, and fluids compared with patients with a BMI less than 25 kg/m2. Although not significant, these investigators found that obese and overweight patients had a trend toward lower mean vasopressin concentrations at 24 and 72 h after a vasopressin infusion compared with those patients with a BMI less than 25 kg/m2(18). These findings suggest that the volume of distribution of vasopressin is affected by BMI, thereby resulting in different vasopressin serum concentrations and presumably variable hemodynamic response. These results are in line with a meta-analysis of critically ill patients which also demonstrated that obese patients (BMI ≥ 30 kg/m2) had significantly lower mortality than patients with a BMI less than 30 kg/m2 (P < 0.001) (19). Despite these findings, our results do not support a connection between weight or BMI and response to vasopressin. The authors of the VASST BMI evaluation theorize that obese patients may have a different pattern of infection and diminished inflammatory response in addition to a potential benefit of decreased exposure to fluids and vasoactive agents (18). The median BMI in the VANISH trial was 26 kg/m2, but there was not stratification by weight or BMI in this trial (17).
Given the lack of mortality benefit associated with vasopressin, recommendations by the SSC Guidelines, and the rising cost of vasopressin, there is greater emphasis on more judiciously selecting this agent. In an effort to minimize cost, institutions are implementing protocols that initiate vasopressin later in the course of septic shock when norepinephrine rates have exceeded 50 mcg/min (20). There is added pressure to identify patient characteristics that are associated with a greater likelihood of response to vasopressin. The current analysis does not support body weight nor body mass index as factors that will influence response to vasopressin.
The results of our analysis are similar to the findings of Lam et al. (11) and Hodge et al. (13). The study by Lam et al. (11) was a single-center, retrospective analysis of 66 medical ICU patients with septic shock who received fixed-dose vasopressin as their only vasoactive agent. Patients were divided into four groups based on their BMI, and the primary outcome assessed was achievement of MAP of at least 65 mmHg 1 h after the initiation of vasopressin. The investigators did not demonstrate a difference in the effectiveness of vasopressin to achieve hemodynamic stability when stratifying patients by BMI, with approximately 80% of all patients achieving hemodynamic stability at 1 h. Similar to the current evaluation, this was a retrospective, single-center analysis of fixed-dose vasopressin which did not find that adjustment for BMI alters the effects of fixed-dose vasopressin on change in MAP and achievement of hemodynamic stability. The study by Lam et al., however, also had many differences from the current evaluation. Vasopressin was evaluated as the initial and only vasopressor, contrary to the current SSC Guideline recommendations (5), and the recommendations during the time of the study period (21). Additionally, based on the SOFA and APACHE II scores, percent of patients who achieved hemodynamic stability with only vasopressin, and mortality rate, it seems that our patient population was more critically ill. Given the methodology and patient population evaluated in this study, the results cannot be extrapolated to our patient population.
In 2012, Miller et al. (12) published a single-center, retrospective study of 64 medical and surgical ICU patients with septic shock who received vasopressor therapy as adjunct to catecholamine administration. The investigators of this study evaluated the effects of a weight-based dose of vasopressin on catecholamine requirements and found that patients who received a higher weight-based dose of vasopressin had lower catecholamine requirements. Despite the investigators concluding that the effect of vasopressin on catecholamine requirements may be effected by body weight, it is unclear if these effects were sustained because hemodynamics were only monitored for the first 4 h after vasopressin initiation and hospital length of stay and mortality was not assessed. Based on APACHE III score, these patients also seemed to be less sick than our patient population and the lack of clinical outcomes assessed makes it difficult to extrapolate these findings.
In the most recent published retrospective, single-center study evaluating the effect of body weight on hemodynamic response in patients with septic shock receiving fixed-dose vasopressin, 40 medical ICU patients were evaluated for the primary outcome of change in MAP after 1 h of vasopressin therapy and the relationship of dose with weight or BMI (13) Similar to the results of our study and Lam et al., no correlation was found between change in MAP at 1 h and vasopressin dose adjusted for weight or BMI. An interesting finding, however, was a strong negative correlation between the change in MAP 6 h after vasopressin initiation and increasing BMI in patients with a BMI at least 30 kg/m2. Our study did not find this same correlation.
In our analysis of the effect of weight and BMI on catecholamine dose and change in MAP in patients with septic shock receiving fixed-dose vasopressin, we sought to address some of the limitations of the previous studies. Our study is the largest cohort to evaluate fixed-dose vasopressin adjusted for both body weight and BMI and the potential impact on both changes in catecholamine dose and changes in MAP. It is challenging to evaluate MAP changes in patients receiving catecholamines as there are likely other factors that can influence MAP and varying monitoring techniques. A more reliable assessment of a patient's response to vasopressin and a potentially more meaningful outcome is the change in catecholamine requirements as we assessed in this analysis. Unlike previous studies, our study included patients in the medical, surgical, and neurosciences ICUs. Our APACHE III and SOFA scores, low achievement of hemodynamic stability, and high in-hospital mortality suggest our patients were more critically ill than previous studies (11, 13). In addition, we followed hemodynamic changes and catecholamine requirements in patients for 12 h and followed long-term outcomes through days 14 and 28 of hospital admission; all of these time points being longer follow-up periods than previous studies (11–13).
Despite attempting to address some of the concerns of previous studies, there are several limitations of our study. This was a retrospective cohort and we relied on complete documentation in the electronic medical record. In addition, this was a single-center study and protocols for vasoactive agent selection and titration are not present at our institution. Therefore, it is possible that the selection and titration of vasoactive agents varied among our patient population, although this is unlikely based on the lack of differences in catecholamine type and quantity at baseline. Although we performed a thorough statistical analysis, we did not complete a power analysis. However, based on a post hoc power analysis, there is unlikely to be a strong correlation (r > 0.3) between BMI and hemodynamic parameters. Another limitation is the statistically significant differences in BMI groups at baseline. Similar to a previous study (22), differences in fluids received, and catecholamine doses can be explained by the differences in weight and BMI. Patients with the highest BMIs received the least amount of fluid before the initiation of vasopressin. This suggests that the initial management of septic shock at our institution could be improved by emphasizing the importance of weight-based fluid goals before initiation of catecholamines, rather than prescribing standard fluid volumes regardless of weight. Patients with BMI less than 30 kg/m2 had more immune suppression, leukemia/myeloma, and ESRD at baseline, thus their higher baseline APACHE III and APS can likely be explained by these differences (23, 24). Alternatively, more patients with a BMI at least 30 kg/m2 had diabetes and COPD, which can likely be explained by their degree of obesity (25). Despite these differences in baseline characteristics, we did not note any differences in our secondary endpoints, suggesting that these differences did not play a role in outcomes.
Overall, this was a well-designed, large, retrospective cohort study that sought to identify a correlation between both weight and BMI and change in catecholamine dose and change in MAP in patients with septic shock receiving fixed-dose vasopressin. Like prior studies, we did not find that BMI or weight impacted response to fixed-dose vasopressin in patients with septic shock, and thus do not recommend adjusting standard fixed-dose vasopressin based on patient weight or BMI. Many unanswered questions regarding vasopressin therapy still exist. Future studies should seek to identify other patient characteristics that may impact response to fixed-dose vasopressin and identify the optimal timing and potential titration of vasopressin in these patients.
In this large cohort of patients with septic shock, adjusting vasopressin dose for weight and BMI had no correlation with change in MAP and catecholamine dose, and fixed-dose vasopressin use led to similar outcomes in patients with differing BMIs. Future studies are warranted to determine if there are other patient factors that could impact the response to fixed-dose vasopressin.
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Keywords:© 2018 by the Shock Society
Body mass index; catecholamine; sepsis; shock; vasopressin; vasopressors; weight