High-dose vasoactive agents in aeromedical retrievals for septic shock: A role for vasopressin?

Objective : To determine the number of patients retrieved by aeromedical teams for septic shock requiring vasopressor support who meet criteria for vasopressin therapy under the Surviving Sepsis Campaign 2021 guidelines. Methods : Retrospective chart review of patients transferred by LifeFlight Retrieval Medicine on vasopressors over 2 years. Results : One thousand one hundred and ﬁ fty-eight patients were retrieved on vasopressor therapy, with 428 requiring infusions for septic shock. One hundred and ﬁ fteen of these met criteria for administration of vasopressin under Surviving Sepsis Campaign guidelines. Conclusion : A suf ﬁ cient percentage of patients on vasopressors for septic shock require vasopressin therapy to meet current best treatment guidelines, and the inclusion of vasopressin in retrieval drug kits should be considered by Australian aeromedical services.


Introduction
Septic shock is a common reason for interhospital transfer via aeromedical retrieval services across Australia. 1 Early vasoactive agents are fundamental in achieving blood pressure targets and organ perfusion, while avoiding fluid overload. 2 The vasopressors available in the Queensland LifeFlight drug kit are adrenaline, noradrenaline and metaraminol. Vasopressin is not included, nor is it carried by other major retrieval services country-wide to the best of our knowledge.
The Surviving Sepsis Campaign (SSC) 3 strongly recommends noradrenaline as the first line agent; vasopressin is recommended as second line in refractory shock, with adrenaline third. There is a deficiency of strong evidence regarding the optimal therapeutic strategy where high-dose or multi-agent vasoactive support is required, 4 but the addition of vasopressin may reduce the adrenergic burden of excessive catecholamine. 5 There is no specific dose of noradrenaline at which the addition of vasopressin is recommended, but the SSC guideline promotes the range of 0.25-0.5 ug/ kg/min as sensible. 3 The SSC guidelines are intended only for application to the adult patient.
We aimed to identify those patients with septic shock who met SSC criteria to receive vasopressin therapy in order to establish the potential role for its inclusion in a retrieval drug kit in the Australian aeromedical setting.

Methods
A retrospective database review was performed to identify patients transported by LifeFlight Retrieval Medicine (LRM) on vasopressors during the 2020 and 2021 calendar years. Handwritten case sheets for each of these encounters were reviewed by FACEM-level investigators to determine the indication for vasopressor therapy; those being managed for sepsis or possible sepsis were further examined. 'Sepsis' was assigned if the diagnosis was confirmed with obvious sepsis physiology, with or without a source or positive blood cultures, and where sepsis was the only impression of the Retrieval Doctor. 'Possible Sepsis' was allocated where the reason for shock was unclear, but sepsis was considered a differential and the empiric treatment included broad-spectrum antibiotics. Where uncertainty existed, the specific case was independently reviewed by a second auditor with a consensus decision made. All adults transported on noradrenaline and/or adrenaline infusions for shock because of sepsis or possible sepsis were included. Patients were considered to have received high dose therapy and would have met criteria to commence vasopressin if the vasopressor infusion rate was >0.25 ug/kg/min or >20 ug/ min, or the patient was receiving dual-agent vasopressor therapy. Exclusions were made for those who received bolus dosing or single agent metaraminol only, for cases where the documentation was inadequate, and for special cases such as ECMO retrievals. Metaraminol is not included in the SSC guidelines and patients receiving single agent metaraminol therapy were excluded from the study. The vasoactive agents used and their respective maximal doses were recorded for each case.

Results
In the 2020 and 2021 calendar years, 12 940 retrievals were conducted. One thousand one hundred and fiftyeight (8.9%) of these received vasopressor therapy. Of those receiving vasopressors, 359 (31%) met criteria for sepsis and 146 (13%) met criteria for possible sepsis. Attrition of this cohort is shown in Figure 1, resulting in a total of 428 cases included for analysis. Sepsis was the most common indication for the use of vasopressor therapy, n = 359 (31%), followed by cardiac causes, n = 164 (14%). The mean cohort age was 64 (SD 14.5) years.
Noradrenaline was the most common vasopressor used, with 365 patients on single-agent noradrenaline infusions and 18 on single-agent adrenaline. Forty-five patients received both noradrenaline and adrenaline infusions.
The median infusion rate for noradrenaline was 10.0 ug/min (IQR 11) and for adrenaline was 10.0 ug/min (IQR 14). Figure 2 demonstrates the frequency of different maximum infusion rates of noradrenaline, which demonstrates significant right skew. Of the patients on vasopressor infusions, 115 (27%) met 'High-dose' criteria; 45 of those had adrenaline and noradrenaline infused concurrently. The remaining 70 had high infusion rates of a single agent (63 noradrenaline, 7 adrenaline). Sixteen patients had both adrenaline and noradrenaline running at high infusion rates (>20 ug/min or 0.25 ug/kg/min). There were 30 patients transferred with vasopressin infusions already commenced at the referring facility. Of these patients, 18 met SSC criteria for vasopressin initiation. Eleven patients had adrenaline or noradrenaline infusions running concurrently running with vasopressin at rates below that suggested for the initiation of vasopressin, although the documentation does not capture if they met criteria at the time of vasopressin commencement. One patient had a single agent vasopressin infusion.

Discussion
The present study provides an analysis of the number of patients who meet SSC 3 criteria for vasopressin administration in an aeromedical retrieval environment. One hundred and fifteen of the 428 patients transferred in septic shock met these criteria, but only 30 of these patients received vasopressin, as it was available at the referring facility. Smaller, rural and regional facilities were unable to commence this therapy, which may represent a health inequality that aeromedical retrieval services could help to address. Vasopressin is presented as a 1 mL ampule, each containing 20 units of drug at a cost of $6.77 per ampule. It has an  approximate 2 year shelf life and does not require refrigeration. The addition of this drug to the retrieval kit would require a smaller stock quantity than stocking all rural facilities and would place the drug administration within the governance structure of critical care retrieval teams.
The study is limited by its retrospective nature, and is reliant on the completeness and accuracy of the data recorded at the time of retrieval. Data regarding the patient's final diagnosis at discharge is not available; however, treatment during care provided by LRM is based on the working diagnosis at the time of retrieval. It is acknowledged that the duration of the infusions at their reported rates is an important omission, because of unavailable data. Further prospective research with focus on patient outcomes is indicated.

Conclusion
Our reviewed demonstrated that 27% of patients undergoing aeromedical retrieval with septic shock met SSC guideline criteria for vasopressin administration. The inclusion of vasopressin in the retrieval drug kit would facilitate increased compliance with the SSC guidelines, which currently represent the best available evidence for the treatment of septic shock.