Clinical Controversy Over Vasopressin in Septic Shock: A Survey of Critical Care Pharmacists

To the Editor:

Significant clinical controversy exists regarding the use of vasopressin in septic shock. The Surviving Sepsis Campaign guidelines recommend vasopressin be added to norepinephrine as a second-line vasopressor to increase mean arterial pressure or to decrease catecholamine requirements. ¹ These recommendations are non-specific regarding precise indications for initiation and discontinuation of vasopressin, and the increasing price of vasopressin influences these decisions for many institutions. We surveyed critical care pharmacists across the nation to determine how clinicians are using vasopressin in septic shock and what factors are included in their decision-making.

Clinical Controversy: What We Know

1. A mortality benefit with vasopressin was observed only in a subgroup of patients with less severe septic shock in the Vasopressin versus Norepinephrine Infusion in Patients with Septic Shock (VASST) study. ² The clinical significance of this finding is unknown, as the subgroup population was not powered for this outcome and the finding has failed to be replicated consistently.

2. Septic shock is associated with a deficiency in endogenous vasopressin, as indicated by a study of 19 patients. ³ To compensate for this physiologic deficit, some have proposed that norepinephrine be weaned first in resolving shock, with vasopressin continued until blood pressure support is no longer required. Several studies have also demonstrated a higher incidence of hypotension after vasopressin discontinuation compared to norepinephrine discontinuation; however, the clinical implications of transient hypotension are unknown and other studies have reported contradictory findings.^4-10 The optimal order of vasopressor discontinuation is unclear.

3. Vasopressin was subject to generic rebranding in 2014 under the U.S. Food and Drug Administration (FDA) Unapproved Drugs Initiative. ¹¹ This resulted in a 50-fold increase in the average daily cost of vasopressin for treatment of septic shock in intensive care units. In response to the increased cost and ambiguous guideline recommendations, some institutions have implemented initiatives to reduce the use of vasopressin based on cost-savings rather than clinical outcomes alone. ¹²

4. A set infusion rate of vasopressin not to exceed 0.03 units/min is recommended by the Surviving Sepsis Campagin; ¹ however, clinicians may rationalize the use of higher rates when reserving this agent for severe shock.

Clinical Controversy: What We Do in Practice

In light of the uncertainties surrounding vasopressin use, we sought to characterize its role in septic shock in clinical practice. A cross-sectional electronic survey was approved by the University of Georgia Institutional Review Board and administered via REDCap. Full details of the research methods and survey questions have been published previously. ¹³ The survey was distributed via email in May 2018 to the American College of Clinical Pharmacy Critical Care Practice and Research Network.

The survey was completed in its entirety by 223 respondents, with the majority practicing in medical or mixed intensive care units at community teaching hospitals distributed across the United States. Nearly all respondents had additional training beyond the Doctor of Pharmacy degree, and 146 (65%) respondents had additional training in critical care (ie, post-graduate year 2 in critical care, fellowship in critical care, and/or board-certified critical care pharmacist certification).

Survey responses indicated wide variability in how vasopressin is used in clinical practice (Table 1). Respondents indicated 23 different methods in which vasopressin is compounded and dispensed in their institutions, with nearly one-quarter of respondents preparing vasopressin doses containing large quantities of drug (50-100 units/dispensed infusion). The majority of respondents (87%) indicated that vasopressin was infused at a set rate at their institution, while 13% of institutions allowed vasopressin to be titrated to achieve hemodynamic goals. Less than one-quarter of respondents, however, reported use of the Surviving Sepsis Campaign-recommended rate of 0.03 units/min.

Table 1.

Pharmacist Perceptions of Vasopressin Use.

Variable	n = 223
Vasopressin dosing
Set rate of 0.03 units/min	46 (21)
Set rate of 0.04 units/min	74 (33)
Set rate of either 0.03 or 0.04 units/min	74 (33)
Other set rate	1 (0.4)
Infusion can be titrated	28 (13)
How is vasopressin dispensed
Compounded 20 units/50 mL	47 (21)
Compounded 20 units/100 mL	37 (17)
Compounded 100 units/100 mL	35 (16)
Compounded 40 units/100 mL	23 (10)
Compounded 40 units/40 mL	17 (8)
Compounded 50 units/50 mL	8 (4)
Compounded 50 units/250 mL	8 (4)
Compounded in other strength	42 (19)
Don’t know	10 (5)
If a patient with resolving septic shock was receiving norepinephrine and vasopressin infusions, which agent would be discontinued first?
Norepinephrine	60 (27)
Vasopressin	126 (57)
Either (no preference)	37 (17)
Assuming norepinephrine was the first line vasopressor, at what rate would you personally consider the ideal time to add a second agent?
Response with non-WBD strategy (µg/min) a	18 ± 9
Response with WBD strategy (µg/kg/min) b	0.53 ± 0.59
Strategies implemented to restrict vasopressin utilization
Formal education of ICU clinicians	44 (20)
Use of more dilute infusion	33 (15)
Restriction to patients requiring a set rate of norepinephrine	26 (12)
Maximum infusion rate of 0.03 units/min	25 (11)
Medication use evaluation	23 (10)
Mandatory approval by clinical pharmacist	6 (3)
Mandatory approval by attending physician	5 (2)
Other strategy	21 (9)
None	114 (51)

Note. Values are presented as number (percentage) or mean ± standard deviation. WBD = weight-based dosing; ICU = intensive care unit.

^an = 163.

^bn = 61.

Respondents were asked two questions assessing clinical protocols and/or practices related to vasopressin use. The ideal threshold to add a second line agent to norepinephrine in septic shock ranged from a norepinephrine rate of 10 to 50 µg/min for respondents using standard norepinephrine dosing, or an even more striking range of 0.1 to 3 µg/kg/min for respondents using weight-based norepinephrine dosing. In a patient with resolving septic shock receiving both norepinephrine and vasopressin, 57% of respondents indicated that they would choose to discontinue vasopressin first.

Half of all respondents indicated that no cost saving strategies related to vasopressin were in place at their institution. In those that did restrict vasopressin utilization, strategies included formal education of ICU clinicians, use of a more dilute vasopressin infusion, restriction to patients requiring a set rate of norepinephrine, setting a maximum infusion rate of 0.03 units/min, and mandatory approval by a clinical pharmacist or attending physician.

Clinical Controversy: What We Should Do Next

In this national survey of critical care clinical pharmacists, great variability in vasopressin use was observed, related to administration, clinical use, and cost containment. Some of these results were consistent with findings by Hammond et al, who surveyed a similar group of critical care pharmacists. ¹⁴ In contrast to Hammond et al, however, we found less emphasis on cost savings. While cost is a key factor in the prescribing of any drug, understanding vasopressin’s clinical utility in septic shock is a priority. The variable responses within our survey and across other studies reflect a need for clear data that can help standardize the use of vasopressors in clinical practice in order to improve efficacy and minimize both adverse effects and unnecessary drug spending. Although vasopressors are “old” drugs with abundant clinical experience, practitioner’s experiences are clearly varied and require further investigation in large-scale, prospective, randomized trials.