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Mean arterial blood pressure target in post cardiac arrest care patients:: ALS New TFSR

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This CoSTR is a draft version prepared by ILCOR, with the purpose to allow the public to comment and is labeled “Draft for Public Comment". The comments will be considered by ILCOR. The next version will be labelled “draft" to comply with copyright rules of journals. The final COSTR will be published on this website once a summary article has been published in a scientific Journal and labeled as “final”.

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.

CoSTR Citation

Skrifvars MB, Holmberg M, Ohshimo S, Berg KM, Drennan I. Mean arterial blood pressure target after cardiac arrest: Consensus on Science with Treatment Recommendations [Internet] Brussels, Belgium: International Liaison Committee on Resuscitation (ILCOR) Advanced Life Support Task Force, 2023, Sept XX. Available from: http://ilcor.org

Methodological Preamble and Link to Published Systematic Review

The topic of hemodynamic goals after cardiac arrest was previously reviewed by the ALS task force in 2015, and an evidence update was conducted in 2020. At that time, consideration of hemodynamic goals was suggested, but there was insufficient evidence to recommend a specific target. Due to the publication of new randomized trials on this topic, the task force decided a systematic review was warranted to update the treatment recommendations for 2024. A recently published systematic review with individual patient data meta-analysis (IPDMA), which includes a meta-analysis of the effect of targeting a MAP higher or lower than 70 mmHg was identified, and this review was deemed of sufficient quality to be used for adolopment (Niemelä 2023). The protocol for that systematic review was published before completion of the review. (Skrifvars 2022 890) An updated search of the literature was done in August 2023 and found no new articles that fit the inclusion criteria. The ALS Task Force considered the results of this IPDMA in formulating updated treatment recommendations.

Systematic Review

Skrifvars MB, Ameloot K, Grand J, Reinikainen M, Hästbacka J, Niemelä V, Hassager C, Kjaergaard J, Åneman A, Tiainen M, Nielsen N, Ullen S, Dankiewicz J, Olsen MH, Jørgensen CK, Saxena M, Jakobsen JC. Protocol for an individual patient data meta-analysis on blood pressure targets after cardiac arrest. Acta Anaesthesiol Scand. 2022 Aug;66(7):890-897.

Niemelä V, Siddiquib F, Amelootc K, Reinikainen M, Grand J, Hästbacka J, Hassager C, Kjaergard J, Åneman A, Tiainen M, Nielsen N, Harboe Olsen M, Kamp Jorgensen C, Juul Petersen J, Dankiewicz J, Saxena M, Jakobsen JC, Skrifvars MB. Higher versus lower blood pressure targets after cardiac arrest: systematic review with individual patient data meta-analysis. Resuscitation 2023 Aug;189:109862

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)

Intervention: Targeting a MAP of 71 mmHg or higher

Comparators: Targeting a MAP of 70mmHg or lower

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 90 to 180 days. Important: ICU mortality, new arrhythmia resulting in hemodynamic compromise or cardiac arrest while in the ICU.

Study Designs: Randomized controlled trials (RCTs) were eligible for inclusion.

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 October 2022 and updated in August 2023.

Risk of bias was assessed with the COCHRANE Risk of Bias tool version 2. While risk of bias was assessed by two authors as part of the published systematic review, a reassessment of the risk of bias was done by two members of the ALS Task Force as part of the adolopment process. The full methodology for the analysis is outlined in detail in the published protocol (Skrifvars 2022) and final manuscript (Niemelä 2023). An updated search of the literature was done in August 2023. The SR included both pooling of aggregate data of four trials and individual patient data (IPD) from three trials. The analysis included aggregate data and individual patient data controlling for study site in the individual trial as well as more advanced models

Consensus on Science

For the critical outcome of mortality at 180-days, four trials including 1065 patients treated after out-of-hospital cardiac arrest (OHCA) provided low certainty evidence (downgraded for risk of bias and indirectness) showing no difference when targeting a higher MAP compared with a lower MAP [risk ratio (RR) 1.08 (95% confidence interval 0.92–1.26]. A total of 195 (36.9%) of 528 participants died in the high MAP group compared with 185 (34.5%) of 537 participants in the low MAP group. The absolute risk difference (ARD) for mortality between the high and low MAP groups was 28 more non survivors/1000 (95% CI 28 fewer to 90 more survivors per 1000).

For the critical outcome of good functional outcome at 180-days, four trials including 1065 patients provided low certainty evidence (downgraded for risk of bias and indirectness) showing no difference when targeting a higher MAP compared with a lower MAP [RR 0.99 (95% CI 0.84-1.16). A total of 320 (60.6%) of 528 participants had a good functional outcome in the higher MAP group vs. 328 (61.1%) of 537 participants in the lower MAP group. The ARD for good functional outcome at 180 days between the high MAP and low MAP groups was 6 fewer patients with a good outcome/1000 (95% CI 98 fewer to 98 more survivors per 1000).

For the important outcome of ICU mortality, four trials including 1065 patients provided very low certainty evidence (downgraded for risk of bias, indirectness and imprecision) showing no difference when targeting a higher MAP compared with a lower MAP [RR 1.09 (95% CI 0.81–1.46)]. A total of 53 (39.3%) of 135 participants died in the ICU in the higher MAP group vs. 51 (36.2%) of 141 participants in the lower MAP group. The ARD for ICU mortality for the high MAP group was 33 more/1000 patients (95% CI 69 fewer to 166 more ICU deaths per 1000).

For the important outcome of a new arrhythmia resulting in hemodynamic compromise or cardiac arrest during ICU stay, four trials including 1065 patients provided very low certainty evidence (downgraded for risk of bias, indirectness and imprecision) showing no difference when targeting a higher MAP compared with a lower MAP [RR 1.04 (95% CI 0.77–1.40)]. A total of 75 (14.8%) of 505 participants experienced the composite outcome of arrhythmia or cardiac arrest during their ICU stay in the higher MAP group vs. 73 (14.3%) of 510 participants in the lower MAP group. The ARD for new arrhythmia resulting hemodynamic compromise or cardiac arrest during ICU stay for high MAP was 6 more/1000 (95% CI 33 fewer to 57 more per 1000)

Treatment Recommendations

There is insufficient scientific evidence to recommend a specific blood pressure goal after cardiac arrest. Therefore, we suggest a mean arterial blood pressure of at least 60-65mmHg in patients after out-of-hospital (moderate to low certainty of evidence) and in-hospital cardiac arrest (low to very low certainty of evidence).

Justification and Evidence to Decision Framework Highlights

This topic was prioritized by the ALS Task Force based on four recent randomized controlled trials on targeting a higher compared to a lower MAP target after cardiac arrest (Jakkula 2017, Ameloot 2019, Grand 2020, Kjaergaard 2022). The trials included 1065 patients treated with either a lower mean arterial blood pressure (MAP) target (70 mmHg or lower ) or higher (higher than 70 mmHg). Only one study was blinded (Kjaergaard 2022) but study endpoints were preplanned (published as protocols) and determined by assessors blinded to the treatment group. The low MAP target in these studies varied from 63 mmHg to 70 mmHg whereas in the higher MAP target group the MAP target varied from 71 mmHg to 100 mmHg. No study made any recommendation on how to target the allocated MAP, but most studies used a continuous infusion of noradrenaline.

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

  • ● The prior treatment recommendation read as follows: “We suggest haemodynamic goals (eg, mean arterial pressure, systolic blood pressure) be considered during postresuscitation care and as part of any bundle of postresuscitation interventions (weak recommendation, low-certainty evidence). There is insufficient evidence to recommend specific haemodynamic goals; such goals should be considered on an individual patient basis and are likely to be influenced by post-cardiac arrest status and preexisting comorbidities”. The four RCTs conducted since that recommendation was formulated provide significant new evidence, but have not yet identified an optimal blood pressure strategy.
  • While no specific mean arterial blood pressure strategy has been found to be beneficial in cardiac arrest trials, the task force thought it was important to provide more specific guidance than had been provided previously. The threshold of 65mmHg was agreed upon as it is the standard in other forms of critical illness and there is no evidence to deviate from that practice in post-arrest patients. Observational data (Bro Jeppesen 2015, Laurikkala 2015, McGuigan 2023) suggest that the lowest MAP not associated with worse outcome after cardiac arrest is around 60-70 mmHg, and the Surviving Sepsis Guidelines recommend targeting a MAP of higher than 65 mmHg in patients with septic shock (Rhodes 2017)
  • We observed no statistically significant benefit from targeting a higher MAP for any critical outcome
  • We observed no statistically significant harm, in relation to the occurrence of a new cardiac arrest or an arrhythmia resulting in haemodynamic compromise, from targeting a higher MAP
  • All RCT studies conducted thus far have focused on patients with a likely cardiac cause of the arrest and a high likelihood of a favorable outcome
  • Whether a higher MAP target, such as 80-100mmHg, may be beneficial for some patients has not been determined by trials to-date. The task force acknowledged that this is part of clinical practice at some cardiac arrest centers.The current treatment recommendation purposefully does not proscribe an upper limit for MAP targets as there is no evidence for this.

Knowledge Gaps

  • All conducted studies have focused on patients with a probable cardiac cause of the cardiac arrest. There is limited evidence as to the optimal MAP in patients not meeting these criteria.
  • Data on MAP targets after in-hospital cardiac arrest are lacking.
  • Data on MAP targets in the pre-hospital setting are lacking.
  • The current evidence can exclude a relative positive or negative treatment effect of targeting a higher MAP of more than 25% but not lower. This difference may unrealistic and there may be a need for larger trials
  • Whether the effect of MAP on outcome could be different in certain sub-groups of patients, such as those with chronic hypertension, is currently unknown.
  • Targeting a higher blood pressure could be beneficial in patients with deranged autoregulation but to date there are limited data on how this could be done in the early hours of care in the ICU which would be needed for it to be used for individualization of the MAP target
  • There are limited data on whether increasing MAP influences cerebral or coronary blood flow
  • There are limited data on whether MAP as opposed to some other proxy for organ perfusion (lactate clearance, urinary output, capillary refill) is the optimal bed-side target
  • The optimal strategy to achieve a target MAP following cardiac arrest is uncertain. This may include use of intravenous fluids (fluid type and volume), specific vasopressors or combinations of vasopressors, and use of mechanical support.

Attachment: MAP target Et D

References:

Ameloot K, De Deyne C, Eertmans W, Ferdinande B, Dupont M, Palmers PJ, Petit T, Nuyens P, Maeremans J, Vundelinckx J, Vanhaverbeke M, Belmans A, Peeters R, Demaerel P, Lemmens R, Dens J, Janssens S, (2019) Early goal-directed haemodynamic optimization of cerebral oxygenation in comatose survivors after cardiac arrest: the Neuroprotect post-cardiac arrest trial. Eur Heart J 40: 1804-1814

Bro-Jeppesen J, Annborn M, Hassager C, Wise MP, Pelosi P, Nielsen N, Erlinge D, Wanscher M, Friberg H, Kjaergaard J; TTM Investigators. Hemodynamics and vasopressor support during targeted temperature management at 33°C Versus 36°C after out-of-hospital cardiac arrest: a post hoc study of the target temperature management trial*. Crit Care Med. 2015 Feb;43(2):318-27.

Grand J, Meyer AS, Kjaergaard J, Wiberg S, Thomsen JH, Frydland M, Ostrowski SR, Johansson PI, Hassager C, (2020) A randomised double-blind pilot trial comparing a mean arterial pressure target of 65 mm Hg versus 72 mm Hg after out-of-hospital cardiac arrest. Eur Heart J Acute Cardiovasc Care 9: S100-s109

Jakkula P, Pettila V, Skrifvars MB, Hastbacka J, Loisa P, Tiainen M, Wilkman E, Toppila J, Koskue T, Bendel S, Birkelund T, Laru-Sompa R, Valkonen M, Reinikainen M, group Cs, (2018) Targeting low-normal or high-normal mean arterial pressure after cardiac arrest and resuscitation: a randomised pilot trial. Intensive Care Med 44: 2091-2101

Kjaergaard J, Møller JE, Schmidt H, Grand J, Mølstrøm S, Borregaard B, Venø S, Sarkisian L, Mamaev D, Jensen LO, Nyholm B, Høfsten DE, Josiassen J, Thomsen JH, Thune JJ, Obling LER, Lindholm MG, Frydland M, Meyer MAS, Winther-Jensen M, Beske RP, Frikke-Schmidt R, Wiberg S, Boesgaard S, Madsen SA, Jørgensen VL, Hassager C, (2022) Blood-Pressure Targets in Comatose Survivors of Cardiac Arrest. N Engl J Med 387: 1456-1466

Laurikkala J, Wilkman E, Pettilä V, Kurola J, Reinikainen M, Hoppu S, Ala-Kokko T, Tallgren M, Tiainen M, Vaahersalo J, Varpula T, Skrifvars MB; FINNRESUSCI Study Group. Mean arterial pressure and vasopressor load after out-of-hospital cardiac arrest: Associations with one-year neurologic outcome. Resuscitation. 2016 Aug;105:116-22.

McGuigan PJ, Giallongo E, Blackwood B, Doidge J, Harrison DA, Nichol AD, Rowan KM, Shankar-Hari M, Skrifvars MB, Thomas K, McAuley DF. Publisher Correction: The effect of blood pressure on mortality following out‑of‑hospital cardiac arrest: a retrospective cohort study of the United Kingdom Intensive Care National Audit and Research Centre database. Crit Care. 2023 May 4;27(1):169.

Niemelä V, Siddiquib F, Amelootc K, Reinikainen M, Grand J, Hästbacka J, Hassager C, Kjaergard J, Åneman A, Tiainen M, Nielsen N, Harboe Olsen M, Kamp Jorgensen C, Juul Petersen J, Dankiewicz J, Saxena M, Jakobsen JC, Skrifvars MB. Higher versus lower blood pressure targets after cardiac arrest: systematic review with individual patient data meta-analysis. Resuscitation 2023 Aug:189:109862.

Nolan JP, Sandroni C, Böttiger BW, Cariou A, Cronberg T, Friberg H, Genbrugge C, Haywood K, Lilja G, Moulaert VRM, Nikolaou N, Olasveengen TM, Skrifvars MB, Taccone F, Soar J, (2021) European Resuscitation Council and European Society of Intensive Care Medicine guidelines 2021: post-resuscitation care. Intensive Care Med 47: 369-421

Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R, Kumar A, Sevransky JE, Sprung CL, Nunnally ME, Rochwerg B, Rubenfeld GD, Angus DC, Annane D, Beale RJ, Bellinghan GJ, Bernard GR, Chiche JD, Coopersmith C, De Backer DP, French CJ, Fujishima S, Gerlach H, Hidalgo JL, Hollenberg SM, Jones AE, Karnad DR, Kleinpell RM, Koh Y, Lisboa TC, Machado FR, Marini JJ, Marshall JC, Mazuski JE, McIntyre LA, McLean AS, Mehta S, Moreno RP, Myburgh J, Navalesi P, Nishida O, Osborn TM, Perner A, Plunkett CM, Ranieri M, Schorr CA, Seckel MA, Seymour CW, Shieh L, Shukri KA, Simpson SQ, Singer M, Thompson BT, Townsend SR, Van der Poll T, Vincent JL, Wiersinga WJ, Zimmerman JL, Dellinger RP. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Intensive Care Med. 2017 Mar;43(3):304-377.

Skrifvars MB, Ameloot K, Grand J, Reinikainen M, Hästbacka J, Niemelä V, Hassager C, Kjaergaard J, Åneman A, Tiainen M, Nielsen N, Ullen S, Dankiewicz J, Olsen MH, Jørgensen CK, Saxena M, Jakobsen JC, (2022) Protocol for an individual patient data meta-analysis on blood pressure targets after cardiac arrest. Acta Anaesthesiol Scand 66: 890-897


mean arterial blood pressure, post cardiac arrest

Discussion

GUEST
Jacob Jentzer

While I would expect that there is limited evidence to support such a recommendation, it would be important to establish whether a blood pressure “ceiling” exists, i.e. a MAP above which worse outcomes occur that could justify blood pressure lowering therapy.

Reply
GUEST
Markus Skrifvars

Markus Skrifvars for the ALS Task Force

In the conducted randomized controlled trials on out-of-hospital cardiac arrest (OHCA) patients where different mean arterial pressures have been targeted, the majority of patients have required a vasopressor to achieve the required pressure (1-4). Therefore, it is unlikely that spontaneous hypertension would have been common during the first 72 hours. However, it needs to be noted that most trials thus far have focused on patients with a cardiac cause of the arrest and the patient have received targeted temperature management and sedation (which may decrease blood pressure). There are some observational studies examining the association between a high blood pressure (spontaneous or induced) and outcome (5,6). In these studies, it appears that hypertension is more common than in the aforementioned randomized trials. In observational trials the blood pressure is commonly collected as a part of a severity of illness score i.e. APACHE/SAPS and is thus the most abnormal (lowest and highest) value over the first 24 hours in the intensive care unit (ICU) (5,6). In general, a high blood pressure (MAP > 104 mmHg, SAP > 156 mmHg) appears associated with worse outcome but the opposite has also been shown (7). There are no RCT examining treatment of hypertension after OHCA. In patients with other types of brain injury the threshold for treating hypertension varies based on the etiology (8). In patients with a haemorrhagic stroke a systolic blood pressure of 140 mmHg is targeted. In patients with ischaemic stroke treatment is not recommended unless the blood pressure is extremely high (>220/120 mmHg) with the exception of those patients who undergo thrombolytic where the target is a blood pressure less than 185/110 mmHg (8). In general ICU patients the general threshold for treatment has been proposed to be 180 mmHg (9). In conclusion, there is insufficient evidence to recommend a specific upper threshold for blood pressure treatment in OHCA patients. Based on indirect evidence one proposed threshold where treatment is considered could be 180 mmHg.

  1. Niemelä et al. Resuscitation 189: 109862
  2. Kjaergaard et al. N Engl J Med 387: 1456-1466
  3. Ameloot et. Eur Heart J 40: 1804-1814
  4. Jakkula et al. Intensive Care Med 44: 2091-2101
  5. Huang et al. Resuscitation. 120:146–52.
  6. McGuigan et al. Crit Care. 27(1):4.
  7. Bro-Jeppesen et al. Crit Care Med. 43(2):318–27.
  8. Guo et al. Am J Hypertens. 35(6):483-499.
  9. Salgado et al. Ann Intensive Care 3(1): 17.
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