Vasopressor choice for managing low blood pressure after cardiac arrest: ALS 3528 TF SR

Conflict of Interest Declaration

The ILCOR Continuous Evidence Evaluation process is guided by a rigorous ILCOR Conflict of Interest policy. The following Task Force members and other authors were recused from the discussion as they declared a conflict of interest: (none applicable)

The following Task Force members and other authors declared an intellectual conflict of interest and this was acknowledged and managed by the Task Force Chairs and Conflict of Interest committees: M. Skrifvars was an author of the systematic review used for the adoplment process. Bias assessments of included studies were done by TF members with no intellectual conflict to mitigate any possible bias. One TF member is an applicant on a grant that aims to compare noradrenaline and adrenaline in the management of low blood pressure in patienst after cardiac arrest.

CoSTR Citation

Insert citation for ILCOR.org posting of CoSTR

Skrifvars MB, Chia YW, O´Neill B, Couper K, Berg K, Dreannan I, on behalf of the ILCOR Advanced Life Support Task Force. Vasoactive medication use after return of spontaneous circulation. Consensus on Science with Treatment Recommendations [Internet] Brussels, Belgium: International Liaison Committee on Resuscitation (ILCOR) Advanced Life Support Task Force, 2023, Nov 10. Available from: http://ilcor.org

Methodological Preamble and Link to Published Systematic Review

The current recommendation for blood pressure targets after ROSC is to target a meart arterial blood pressure (MAP) of higher than 60-65 mmHg. Vasopressor agents are commonly used to maintain blood pressure after return of spontaneous circulation (ROSC). One important knowledge-gap acknowledged in the Consensus on Science with Treatment Recommendations CoSTR) on MAP targets was that there is limited data on the ways to achieve and maintain MAP goals after ROSC. ILCOR has not previously undertaken any systematic review on what the best vasopressor is to manage blood pressure in patients with return of spontenous circulation (ROSC) after cardiac arrest. The purpose of the current review was to gather evidence on the choice of vasopressor in patients after ROSC. The current systematic review was registered at Prospero (CRD42024549394) prior to undertaking the search.

Systematic Review

Milla Jousi, Ville Niemelä, Yew Woon Chia, Johanne Juul Petersen, Sarah Klingenberg, Keith Couper, Christina Silassen, Brian O´Neill, Caroline Kamp, Janus Jacobssen, Markus B Skrifvars. Vasopressor use after return of spontaneous circulation – A systematic review. Manuscript in preparation.

Markus Skrifvars, Yew Woon Chia, Keith Couper and Brian O´Neill are members of the ILCOR Advanced Life Support Task Force.

PICOST

The PICOST (Population, Intervention, Comparator, Outcome, Study Designs and Timeframe)

Population: Adults with sustained ROSC after cardiac arrest (out-of-hospital or in-hospital) and a need for a vasopressor infusion to manage low blood pressure

Intervention: Vasopressor or a combination of vasopressors provided intravenously as an infusion after ROSC

Comparators: No vasopressor, a different vasopressor or a different combination of vasopressors provided intravenously as an infusion after ROSC

Outcomes: Critical: survival or good functional outcome defined as a modified Rankin score (MRS) 1-3 or cerebral performance category (CPC) scale 1-2 at longest time-point (author defined). Important: ICU or ED mortality, new arrhythmia resulting in hemodynamic compromise or cardiac arrest while in the ED or ICU.

Study Designs: Human randomized controlled trials (RCTs) and non-randomized studies (non-randomized controlled trials, interrupted time series, controlled before-and-after studies, cohort studies and case series) will be included. Unpublished studies, conference abstracts, trial protocols editorials, comments, letters to the editor are excluded. Animal studies are excluded. All relevant publications in any language are included as long as there is an English abstract or full-text article available.

Timeframe: All years and all languages were included as long as there was an English abstract; unpublished studies (e.g., conference abstracts, trial protocols) were excluded. The literature search was conducted in August 2024.

Risk of bias was assessed with in the randomized controlled trial with the COCHRANE Risk of Bias tool version 2 and observational studies with the ROBINS-I tool. Risk of bias was assessed by two authors part of this working group (Yew Woon Chia and Brian O´Neill)

Attachments: ALS 3528 Vasopressor choice PRISMA flow chart; ALS 3528 Should noradrenaline vs adrenaline be used for low blood pressure after return of spontaneous circu 2, ALS 3528 Should dopamine vs dopamine in combination with noradrenaline or adrenaline be used; ALS 3528 Vasopressor choice Risk of bias assessment;

Consensus on Science

The search identified initially at total of 50,240 studies out of which 7,048 were screened, and after full text review, a total of 8 studies were included. There was a wide variation in the reporting of the results with regards to the possibility to perform a meta-analysis. Because of variety in reporting of survival at different time points it was decided to use survival and functional outcome at longest follow-up as the main outcome. In general this meant reporting together survival at 30 days and hospital survival. In addition three different comparisons were perfomed; noradrenaline compared to adrenaline, noradrenaline compared to dopamine and dopamine compared to dopamine combined with a different vasopressor such as noradrenaline or adrenaline. These three comparisons are presented separately.

Comparison of noradrenaline to adrenaline

For the critical outcome survival at 180 days

For the critical outcome of mortality at 180-days we found no trials reporting these outcomes in patients treated with noradrenaline compared to any other vasopressor.

For the critical outcome functional outcome at 180 days

For the critical outcome of functional outcome at 180-days we found no trials reporting these outcomes in patients treated with noradrenaline compared to any other vasopressor.

For the critical outcome survival at at thirty days or hospital survival (survival at longest time point)

We found one randomized controlled study ¹ (high risk of bias) including 40 patients treated after non-traumatic cardiac arrest randomized with a post-ROSC MAP less than 65 mmHg randomized to treatment with either noradrenaline or adrenaline. There 30-day mortality was 90% in the noradrenaline and 90% in the adrenaline group (p=1.0).

We found one retrospective study ² (moderate risk of bias) including 766 OHCA patients with 481 treated with noradrenaline and 285 treated with adrenaline during care in the intensive care unit. The use of adrenaline was associated with higher mortality (adjusted OR 2.6 95% CI 1.4–4.7) and higher likelihood of unfaroable neurologic outcome (adjusted OR 3.4 95% CI 2.4–5) at hospital discharge.

We found one retrospective study of 221 OHCA patients ³ (serious risk of bias) of whom 151 were treated with noradrenaline and 70 with adrenaline. The use of adrenaline was assoaciated with higher in-hospital mortality (adjusted OR 6.2 95% CI 2.4–16.3).

We found one retrospective study ⁴ (moderate risk of bias) including 451 OHCA patients with ROSC and shock in the pre-hospital setting receiving vasopressor infusions, 253 (56%) received norepinephrine and 198 (44%) received epinephrine infusions. There was no difference in survival to hospital discharge (adjusted OR 1.08 95% CI 0.60-1.93) or good neurologic function (adjusted OR 0.89 95% CI 0.45-1.77).

We found one retrospective study ⁵(moderate risk of bias) including 1,893 patients of whom 1,010 (53.4%) received prehospitally an adrenaline infusion and 883 (46.7%) an noradrenaline infusion. There was no difference in survival between those treated with adrenaline compared to noradrenaline (adjusted OR 1.0 95% CI 0.6-1.7).

For the important outcome of emergency department death

We found one study including 93 patients ⁶ (moderate risk of bias) of whom 45 were treated with noradrenaline and 42 with adrenaline the use of adrenaline compared to noradrenaline was associated with a higher likelihood of death, rearrest and failure to achieve a stable blood pressure (adjusted OR 3.9 95% CI 1.4-12.2).

For the important outcome of rearrest in the pre-hospital setting, emergency department or intensive care unit

We found one retrospective study ² (moderate risk of bias) including 766 patients with 481 treated with noradrenaline and 285 treated with adrenaline during care in the intensive care unit. The rate of rearrest was 9% in the patients treated with adrenaline and 3% in the patiets treated with noradrenaline. No adjusted odds ratios were reported.

We found one study of 93 OHCA patients ⁶ (moderate risk of bias) of whom 45 were treated with noradrenaline and 42 with adrenaline, the rearrest rates were 17 (37.8%) and 18 (42.9%) respectively. No adjusted odds ratios were reported.

We found one retrospective study of 221 OHCA patients ³ (serious risk of bias) of whom 151 were treated with noradrenaline and 70 with adrenaline. The likelihood of rearrest was higher in the patients treated with adrenaline (adjusted OR 5.77 95% CI 2.7–12.2).

We found one retrospective study ⁴ (moderate risk of bias) including 451 OHCA patients with ROSC and shock in the pre-hospital setting receiving vasopressor infusions, 253 (56%) received noradrenaline and 198 (44%) received adrenaline infusions. The rearrest rates were 54.5% (108) with adrenaline and 25.3% (64) with noradrenaline. The likelihood of rearrest was higher with adrenaline (adjusted OR 3.4 95 CI% 2.3-5.1).

We found one retrospective study ⁵ (Smida 2024) (modeate risk of bias) including 1,893 patients of whom 1,010 (53.4%) received an adrenaline infusion and 883 (46.7%) an noradrenaline infusion. There was no difference in rearrest rates between those treated with adrenaline compared to noradrenaline (adjusted OR 0.93 95% CI 0.72-1.21).

Comparison of noradrenaline to dopamine

For the critical outcome survival at 180 days

We found no trials reporting survival at 180 days in patients treated with noradrenaline compared to dopamine.

For the critical outcome functional outcome at 180 days

We found no trials reporting functional outcome at 180-days in patients treated with noradrenaline compared to dopamine.

For the critical outcome survival at thirty days

We found one retrospective study ⁷ (serious risk of bias) including 1011 patients of whom 670 patients with post ROSC shock were treated with dopamine only, 92 with noreadrenaline only and 294 with both noradrenaline and dopamine. The use of noradrenaline compared to dopamine was not associated with any difference in thirty day survival (adjusted OR 1.0 95% CI 0.48-2.06) or favorable functional outcome (adjusted OR 0.8 95% CI 0.28-2.53).

For the important outcome of rearrest in the pre-hospital setting, emergency department or intensive care unit

We found no studies reporting rearrest rates in patients receiving noradrenaline compared to dopamine.

Comparison of dopamine to dopamine and noradrenaline or adrenaline

For the critical outcome survival at 180 days

We found no studies reporting mortality at 180-days we found no trials reporting this outcome in patients treated with dopamine compared to dopamine combined with noradrenaline or adrenaline.

For the critical outcome functional outcome at 180 days

We found no studies reporting functional outcome at 180-days we found no trials reporting this outcome in patients treated with dopamine compared to dopamine combined with noradrenaline or adrenaline.

For the critical outcome survival at thirty days

We found one retrospective study ⁷ (serious risk of bias) including 1011 patients of whom 670 patients with post ROSC shock were treated with dopamine only, 92 with noreadrenaline only and 294 with both noradrenaline and dopamine. The use of noradrenaline together with dopamine compared to dopamine alone was not associated with any difference in thirty day survival (adjusted OR 0.6 95% CI 0.3-1.1) but was associated with less patients with favorable outcome (adjusted OR 95% CI 0.2 0.04-0.78).

We found one retrospective study ⁸ (serious rsk of bias) including 310 patients, 174 patients (56%) received dopamine only and 136 (44%) received dopamine together with noradrenaline or adrenaline. The use of dopamine together with noradrenaline or adrenaline was associated with higher 30-day mortality than dopamine alone (adjusted OR 2.0 95% CI 1.3–3.0).

For the important outcome of rearrest in the pre-hospital setting, emergency department or intensive care unit

We found no studies reporting rearrest rates in patients treated with dopamine compared to dopamine combined with noradrenaline or adrenaline.

Treatment Recommendations

There is insufficient evidence to recommend a specific vasopressor to treat low blood pressure in patients after cardiac arrest.

Justification and Evidence to Decision Framework Highlights

This topic was prioritized by the ALS Task Force given the lack of a CoSTR and treatment recommendation on this topic. Recent studies on different blood pressure targets have been published and a COSTR on the blood pressure target after cardiac arrest was finalized in 2023.

In making these changed recommendations, the ALS Task Force considered the following:

• The evidence for the choice of different vasopressors is of very low certainty. There is only one small randomized controlled trial and all observational trials are very likely to be prone to “confounding by indication” i.e. adrenaline is only used in the most critically and unstable patients. This makes it difficult to draw firm conclusions on the differences between the effect of adrenaline and noradrenaline on outcome.

• There was disagreement on the TR with some members suggesting a recommendation of noradrenaline as the first line vasopressor (7 members) and some suggested the current one of limited evidence to make a recommendation (9 members).

• ● The evidence do not show any consistent benefit from either adrenaline o noradrenaline and therefore the majority of the TF members felt that it is not possible to make any specific TR favoring a special vasopressor over another one.
• ● The feasibility of giving different vasopressors likely vary a great deal between settings. This review identified two studies conducted in the pre-hospital setting ^4,5. In these studies survival was similar in patients treated with noradrenaline compared to adrenaline, and one study suggested more rearrests with adrenaline.

• Vasopressors are commonly used to manage blood pressure in other critically ill patients. The latest “Surviving Sepsis Campaign Guidelines” recommend noradrenaline as the first line vasopressor ⁹.

• Vasopressors are commonly used for the management of low blood pressure and low cardiac output in patients with cardiogenic shock. The recommendations for the first line vasopressor for the management of low blood pressure is noradrenaline in some guidelines (ESC Guidelines for the Diagnosis and Treatment of Acute and Chronic Heart Failure, ESC Guidelines for the Management of Acute Myocardial Infarction in Patients Presenting with ST-Segment–Elevation, AHA AMI-CS, Invasive Management of Acute Myocardial Infarction Complicated by Cardiogenic Shock: A Scientific Statement from the American Heart Association) and noradrenaline or dopamine in one (AHA CS, Contemporary Management of Cardiogenic Shock: A Scientific Statement from the American Heart Association) ^10-12.

• In patients with cardiogenic shock and acute myocardial infarction one study of 57 patients randmomized to treatment with noradrenaline or adrenaline as the first line vasopressor was stopped prematurely due to a higher incidence of refractory shock with the use of adrenaline ¹³.

• The effect of noradrenaline and adrenaline on brain circulation and cerebral blood flow are unknown

• One study conducted in 280 critically ill patients with low blood pressure randomized patients to treatment with either noradrenaline or adrenaline and found no difference in outcome but more treatment withdrawals in the adrenaline group given metabolic effects ¹⁴.

Knowledge Gaps

• The evidence is very limited with only one small RCT including 40 patients ¹.
• All studies were conducted in out-of-hospital cardiac arrest patients, whether these findings are generalizable to inhospital cardiac arrest patients is currently unclear
• It is clear that there are variability in vasopressor availability between settings and countries and this will influence use.
• Some systems and in some clinical settings intermittent bolus administration of vasopressors to treat low blood pressure may be preferable but there is no data on this. As adrenaline admisnistered as a bolus is recommended during cardiopulmonary resuscitation to continue with administration of small adrenaline boluses during transport could be an readily available option but the review identified no studies on this.
• Some pre-hospital systems use only one vasopressor such as adrenaline in critically ill patients during transport and it is unclear whether any change of practice in those patients after cardiac arrest would be beneficial. Variablility exists in local guidelines on the administration of infusions of vasopressors into a peripheral vein or central vein.
• This COSTR does not address using intravenous fluid boluses to increase blood pressure alone or in combination with vasopressors.
• There is limited data on the use of “pure” inotropes such as dobutamine, levosimendan or milrinone together with vasopressors to increase blood pressure and to increase the cardiac output.
• This COSTR does not address the use of vasopressors in patients undergoing mechanical support

ETD summary table: ALS 3528 Etd Table choice of vasopressors

References

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