High-normal versus low-normal mean arterial pressure thresholds in critically ill patients: A systematic review and meta-analysis of randomized trials

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High-normal versus low-normal mean arterial pressure thresholds in critically ill patients: A systematic review and meta-analysis of randomized trials

https://doi.org/10.21203/rs.3.rs-1627487/v1

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Targeted blood pressure thresholds remain unclear in critically ill patients. Two prior systematic reviews have not demonstrated differences in mortality with a high mean arterial pressure (MAP) threshold but they only included patients with septic shock. Thus, we conducted an updated systematic review and meta-analysis of randomized controlled trials (RCTs) that compared the effect of a high-normal versus low-normal MAP on mortality in all pertinent disease states for critically ill patients.

We searched six databases from inception until September 5th 2021 for RCTs of critically ill patients targeted to either a high-normal (≥ 65 mm Hg) versus a low-normal (≥ 60 mm Hg) MAP threshold for at least 24-hours. We assessed study quality using the RoB-2 tool and the risk ratio (RR) was used as the summary measure of association.

We included 7 RCTs with 3772 patients. Three trials were conducted in patients following out-of-hospital cardiac arrest, two in distributive shock, one in septic shock, and one in hepatorenal syndrome. The pooled RR for mortality was 1.06 (95%CI 0.98 to 1.17). There was no significant between-study heterogeneity (I² = 0%, 95%CI: 0 to 47%). Furthermore, there was no difference in the rates of favourable neurologic outcome or renal replacement therapy between the high-normal versus low-normal MAP groups.

This systematic review and meta-analysis demonstrates that there is no difference in mortality amongst critically ill patients targeted to a high-normal versus low-normal MAP target.

high-normal MAP target

critically ill

mortality

Increasing mean arterial pressure (MAP) to optimize cardiac output and tissue perfusion is central to the resuscitation strategy of critically ill patients [1]. The surviving sepsis guidelines have a strong recommendation to target a MAP of at least 65 mmHg in patients with septic shock who require vasopressors [2]. In recent years, this ‘one size fits all’ approach to MAP targets has been challenged and several publications have assessed the effect of higher MAP targets on clinical outcomes such as mortality and the need for renal replacement therapy [1, 3, 4].

In 2019, a study of critically ill septic shock patients demonstrated a lower mortality when MAP was maintained between 75-85mmHg amongst those with a history of chronic hypertension [4]. Concurrently, a 2019 randomized controlled trial (RCT) demonstrated that targeting a MAP of 85–100 mmHg did not mitigate secondary ischemic brain injury following resuscitation from cardiac arrest and did not improve neurologic outcome [5]. In order to achieve higher MAP targets, higher doses of vasopressors are often required and this can have adverse effects including organ ischemia, hyperglycemia, hyperlactatemia, and arrhythmias [6].

Two systematic reviews and meta-analyses of have sought to determine if high MAP targets improve mortality in critically ill patients [7, 8]. However, both studies only included patients with septic shock and thus, did not assess the effect of a high MAP strategy in other critically ill patients.

Thus, we conducted a systematic review and meta-analysis of randomized controlled trials to determine the pooled estimate of comparing a high-normal to low-normal MAP target on mortality in critically ill patients.

This systematic review and meta-analysis was registered on PROSPERO (CRD 307604) and is reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines [9].

Information sources and search strategy

We searched the following electronic databases for published works from inception to September 5th 2021: MEDLINE (Ovid), EMBASE (Ovid), Evidence-Based Medicine Reviews (Ovid), CINAHL (EBSCO) and Web of Science. We also searched ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform for unpublished works and ongoing trials. Finally, we searched conference abstracts for the following meetings: Society of Critical Care Medicine, American Thoracic Society and the European Society of Intensive Care Medicine from conference inception to 2021. Our search strategy used a combination of Medical Subject Heading (MeSH) and text word terms for the following three concepts: blood pressure, critically ill patients and randomized trials. The search strategy is presented in Appendix 1 (Electronic Supplementary Material).

Selection process

We included RCTs that included critically ill adults ≥ 16 years of age admitted to a critical care unit who were in shock or had hypotension requiring vasopressor support. Studies had to randomize patients to a blood pressure target of ≥ 65mmHg in the experimental group and ≥ 60mmHg in the control group. The studies had to maintain the MAP targets for at least 24-hours and present mortality as an outcome. There were no language restrictions.

Study Selection

Using a two-stage selection process, three reviewers (KR, CR, and DG) independently and in duplicate screened abstracts using the inclusion and exclusion criteria above. Following abstract screening, the reviewers independently reviewed each full text before collaboratively making decisions on which studies to include. Disagreements were discussed before making final unanimous decisions on study inclusions.

Data collection and risk of bias assessment

Two reviewers (KR and DG) used a pre-formatted spreadsheet (Microsoft Excel®, Redmond Washington, USA) to collect data on the study design, inclusion and exclusion criteria, randomization, blinding, MAP targets in the control and intervention groups, duration for which MAP was maintained, mortality at 180 days or at a time point closest to 180 days, and secondary outcomes including neurological outcome at any time point, use of renal replacement therapy, and frequency of vasopressor induced adverse events. We used Graph Grabber 2.0.2 to digitize graphs and extract data points for achieved MAP and vasopressor doses.

Study quality was assessed by two reviewers (KR and CR) using the RoB-2 tool [10]. Studies were rated on their risk of bias in four domains: (1) randomization process, (2) deviations from the intended interventions, (3) missing outcome data, and (4) measurement of the outcome.

Data synthesis

We used the risk ratio (RR) as the summary measure of association for mortality. The random-effects method of Dersimonian and Laird was used to generate the pooled RR across studies [11]. We a priori chose to present a summary measure of association when there were 5 or more studies presenting an outcome of interest. We assessed for between-study statistical heterogeneity using Cochrane’s Q-statistic, with a P less than 0.10 being considered significant. Heterogeneity was quantified using the I² statistic and 95% confidence intervals [12].

Study selection and characteristics

We identified 4989 studies (Fig. 1). After duplicate removal and abstract screening, 22 articles underwent full-text review. We included 7 studies with a total of 3772 patients in our meta-analysis [5, 13–18].

Table 1 lists the characteristics of the included trials. Five trials were conducted in Europe [5, 13, 15, 17, 18] and 2 in North America [14, 16]. Three trials were in patients with out-of-hospital cardiac arrest [5, 15, 17], two trials were patients with vasodilatory shock requiring vasopressors [14, 18] and one trial each were of patients with septic shock [13] and hepatorenal syndrome [16]. The most frequent vasopressor used across all studies was norepinephrine.

Characteristics of blood pressure thresholds used in the trials

In six studies, the MAP targets in the intervention (high-normal) groups were ≥ 72 mm Hg and > 60 mm Hg in the control (low-normal) group [5, 13–17]. In one study, the MAP target in the control group was specified as ‘usual care,’ while the MAP target in the intervention group was 60-65mmHg [18]. For our analysis, we specified the ‘usual care’ arm as the high-normal group. Duration of MAP targets in each study ranged from 36 hours to 7 days.

Three RCTs achieved the targeted MAP thresholds in both the high-normal and low-normal arms [5, 15, 17] and achieved separation between groups of 6 mm Hg [17], 12 mm Hg [15], and 14 mm Hg [5]. In 3 RCTs, the actual MAP was higher than the threshold in the low-normal arm [13, 14, 18]. In one RCT, the actual MAP was below the target in the high-normal arm, and higher than the target in the low-normal arm [16]. In this RCT, the separation between arms was 13 mm Hg over the study period.

Risk of bias assessment

Results from the RoB-2 are presented in Appendix 2 (Electronic Supplementary Appendix). All included studies had some concerns of bias [5, 13–18].

Mortality

Mortality was reported in all seven trials and the Forest plot is presented in Fig. 2. Only three trials presented mortality at our pre-specified interval of 180 days [5, 14, 17]. Thus, we used the following mortality outcomes for the other studies: in-hospital [16], 28-day [18], 30-day [15], and 90-day [13]. The pooled RR across studies was 1.06 (95%CI 0.98 to 1.14). There was no statistical between-study heterogeneity in our primary analysis (Q = 1.07, P = 0.98) corresponding to an I² of 0% (95%CI 0 to 71). Performing a leave-one-out meta-analysis resulted in no meaningful change on the final point-estimate (results not shown).

Favourable neurological outcome & use of renal replacement therapy

Only three studies reported neurological outcome [5, 15, 17]. As such, we did not perform a pooled analysis. The point estimates for the individual studies are presented in Fig. 3. There was no difference in the rates of favourable neurologic outcome between the high-normal and low-normal MAP groups in any trial. Similarly, only 3 studies reported rates of renal replacement therapy [13, 17, 18] and the point estimates for the individual studies are presented in Fig. 3. There was no difference in the rates of renal replacement therapy between the high-normal and low-normal MAP groups in any trial.

Rates of adverse vasopressor events

Three studies reported rates of vasopressor-associated adverse events [5, 13, 18] (Appendix 3, Electronic Supplementary Material). The most frequently reported adverse events were cardiac dysrhythmias. There was no difference in the overall rates of adverse vasopressor events between the high-normal and low-normal MAP groups in any trial.

In this systematic review and meta-analysis of RCTs of critically ill patients, there was no significant difference in mortality between patients targeted to high-normal versus low-normal MAP. Furthermore, there was no between-study heterogeneity in the mortality outcome. Although we did not perform a pooled analysis, there was no difference in either favourable neurological outcome or need for renal replacement therapy in any of the included studies. Finally, there did not appear to be any difference in the rates of adverse vasopressor events between the high-normal and low-normal MAP groups.

Studies examining MAP targets in critically ill patients have yielded conflicting results. A systematic review of 9 observational studies suggested that higher MAP targets were associated with improved neurologic outcomes in patients with cardiac arrest [19]. While a pooled analysis was not performed in that systematic review due to marked between-study heterogeneity, 7 of 9 studies demonstrated that a higher blood pressure was associated with improved outcomes. In contrast, an individual patient meta-analysis of two RCTs [13, 14] in hypotensive patients requiring vasopressor therapy showed that high-normal MAP targets were not associated with lower mortality (RR 1.1, 95% CI: 0.90 to 1.2) [8]. This result was not modified by either age or pre-morbid hypertension. In fact, a post-hoc analysis of this individual patient meta-analysis suggested that mortality may be higher in those patients who require vasopressors for longer than 6-hours [20]. In the intervening time since the publication of this pooled analysis, several more RCTs have been published, which was the rationale behind our current study.

While we observed no benefit to a high-normal MAP strategy, this differs from the possible benefit observed in the systematic review by Bhate and colleagues [19]. As their systematic review was restricted to studies of patients admitted following cardiac arrest, difference in the patient populations could be an explanation for these conflicting results. However, our current study included three RCTs of patients following cardiac arrest, none of which demonstrated any difference in mortality with a high-normal MAP strategy. It must be noted that none of these included RCTs were powered to detect differences in mortality. Finally, the difference observed between our meta-analysis and the systematic review by Bhate and colleagues may be in the design of the included studies. Whereas our study included only RCTs, Bhate and colleagues performed a systematic review of observational studies, which is thus subject to residual confounding.

It is important to note that in all the included RCTs, the low-normal MAP groups achieved a MAP target higher than was intended. Thus, the separation in MAP between the high-normal versus low-normal groups was smaller than anticipated, and in some studies was less than 10mmHg [13, 14, 17, 18]. This may have contributed to the lack of difference in outcomes between the two groups. Furthermore, while there was no significant statistical heterogeneity between the included studies, there was clear clinical heterogeneity between the included study populations. The small effect sizes and low study numbers may have led to a low measured statistical heterogeneity and thus, may not accurately reflect the heterogeneity between studies.

None of the RCTs included in our systematic review demonstrated an association with either neurologic outcome or need for renal replacement therapy. In the SEPSISPAM trial (included in this analysis), there was an effect measure modification between MAP assignment and chronic arterial hypertension on the need for RRT (P-interaction 0.04) [13]. Unfortunately, because of the pooled nature of our study, we were unable to examine for any important subgroups.

In addition to the aforementioned limitations, one of the studies included in our meta-analysis randomized patients to a strategy of permissive hypotension compared to a MAP threshold at the discretion of the attending physician [18]. Although this intervention is fundamentally different that the other included trials, we chose to include this trial as there was still a difference in MAP between the two arms, and the MAP in the permissive hypotension arm was above 60 mm Hg. Thus, despite the different intervention, we feel including this trial still informs to the fundamental question of different MAP thresholds.

This systematic review and meta-analysis demonstrated that there was no significant difference in mortality amongst critically ill patients treated with high-normal compared to low-normal MAP targets. Despite limited between-study heterogeneity, there was still risk of bias in the included studies. This study does not support a high-normal MAP threshold in critically ill patients. Future studies to help delineate either individualized MAP strategies or important subgroups are warranted.

Ethics Approval and Consent to participate

Not applicable

Data Availability Statement

All data generated or analysed during this study is included in this manuscript and its supplementary information files.

Competing Interests

Donald Griesdale is supported by the Michael Smith Foundation for Health Research Health Professional Investigator award. Mypinder Sekhon is supported by the Michael Smith Foundation for Health Research Health Professional Investigator award and the Vancouver Coastal Health Research Institute Clinician Scientist award.

Funding

Not applicable

Authors’ Contributions

All authors contributed to the study conception, design and production. The literature search was performed by KR, CR and DG while data analysis was performed by DG. All authors were involved in production and critical revision of the study.

Acknowledgements

We would like to acknowledge the members of the UBC Division of Critical Care for their guidance and support.

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Evans L, Rhodes A, Alhazzani W et al (2021) Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock. Crit Care Med 111:e1063-e1143. doi: 10.1097/CCM.0000000000005337
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Table 1

Characteristics of included trials
Author, Yr (Country) Number of patients (centres)	Population (age) Injury severity score	High-Normal MAP target (in mm Hg)	Low-Normal MAP target (in mm Hg)	Duration of intervention	Vasopressor dose	Mortality Outcome
		Achieved MAP	Achieved MAP
Asfar, 2014 (France) n = 776 (29 centres)	Septic shock (≥ 18 years) SOFA: mean 10.8 (SD 3.1)	80–85	65–70	Maximum 5 days, or until weaned from vasopressor support	Norepinephrine, epinephrine (1 centre) Median dose (ug/kg/min) day 1–5: H: 0.58, 0.38, 0.14, 0.03, 0.01 LN: 0.45, 0.16, 0.02, 0.00, 0.00	28 day mortality
		Mean (95%CI) 85 (83–86)*	Mean (95%CI) 76 (73–78)*
Lamontagne, 2016 (Canada & US) n = 118 (11 centres)	Vasodilatory shock receiving vasopressors (≥ 16 years) APACHE II: mean 25 (SD 7)	75–80	60–65	Until MAP within or above target without vasopressors Median (IQR) duration vasopressors: H: 5 (3–8) days LN: 3 (2–5) days	Norepinephrine (92%), Vasopressin (48%), Phenylephrine (14%), Dopamine (4%) Daily norepinephrine equivalent dose: H: 14 (8–29) mg LN: 10 (2–19) mg	Mortality at ICU discharge, 28 days, hospital discharge, and at 6 months
		Mean (SD) 79 (5)	Mean (SD) 70 (5)
Jakkula, 2018 (Finland & Denmark) n = 120 (7 centres)	OHCA with VF/VT as initial rhythm (18–80 years) APACHE II: median 28 (SD 5)	80–100 (63)	65–75 (60)	36h from ICU admission or until extubation or spontaneous ventilation	Norepinephrine dose, median (IQR): H: 0.13 (0.08–0.20) ug/kg/min LN: 0.05 (0.02–0.11) ug/kg/min	Vital status at 30 days post arrest
		Median (IQR) 84 (80–90)*	Median (IQR) 72 (69–76)*
Ameloot, 2019 (Belgium) n = 107 (2 centres)	OHCA, cardiac etiology (≥ 18 years) SOFA: mean 9.5 (SD 2.7)	85–100 (along with SVO2 65–75%)	≥ 65	36h from ICU admission	Norepinephrine mean (95%CI)*: H: 0.25 (0.13–0.41) ug/kg/min LN: 0.13 (0.05–0.27) ug/kg/min	180 day mortality
		Mean (95%CI) 87 (76–88)*	Mean (95%CI) 73 (60–85)*
Varajic, 2019 (US) n = 18 (1 centre)	Hepatorenal syndrome (≥ 18 years) MELD: mean 33 (SD 7)	≥ 85	65–70	4 days	Norepinephrine, phenylephrine, vasopressin Median (IQR) daily dose norepinephrine* H: 0.03 (0–0.23) ug/kg/min LN: 0.07 (0–0.37) ug/kg/min	In hospital mortality
		Median (IQR) 84 (77–92)*	Median (IQR) 71 (66–77)*
Lamontagne, 2020 (UK) n = 2583 (65 centres)	Vasodilatory shock receiving vasopressors (≥ 65 years) APACHE II: mean 20.7 (SD 6.3)	MAP target at discretion of treating clinicians	Permissive hypotension 60–65	7 days Median (IQR) vasopressor duration in hours): H: 38 (19–67.0) LN: 33 (15–56)	Norepinephrine, Metaraminol, Vasopressin, Epinephrine, Phenylephrine, Terlipressin, Dopamine. Norepinephrine total daily equivalents, median (IQR): H: 26.4 (8.9–65.6) mg LN: 17.7 (5.8–47.2) mg	All cause mortality at 90 days, mortality at ICU discharge, survival to longest follow up
		Median MAP (IQR) while on vasopressors 73 (69–77)	Median MAP (IQR) while on vasopressors 67 (65–70)
Grand et al, 2020 (Denmark) n = 50 (1 centre)	OHCA, GCS ≤ 8, presumed cardiac cause (≥ 18 years)	72	65	72 hours Median (IQR) Vasopressor duration in days: H: 2 (1–4) LN: 2 (2–3)	Norepinephrine, Dopamine Norepinephrin mean (IQR) dose in 1st 24 hrs: H:0.13 (0.11–0.21) ug/kg/min LN:0.08 (0.05–0.19) ug/kg/min	180 day mortality
		Mean 79 (range of means 67–98)*	Mean 73 (range of means 64-85)*

H = High MAP group; LN = Low-Normal MAP group; * = data extracted using Graph Grabber 2.0.2; IQR = interquartile range; SD = standard deviation; 95%CI = 95% confidence interval

No competing interests reported.

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High-normal versus low-normal mean arterial pressure thresholds in critically ill patients: A systematic review and meta-analysis of randomized trials

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Abstract

Figures

Introduction

Materials & Methods

Information sources and search strategy

Selection process

Study Selection

Data collection and risk of bias assessment

Data synthesis

Results

Study selection and characteristics

Characteristics of blood pressure thresholds used in the trials

Risk of bias assessment

Mortality

Favourable neurological outcome & use of renal replacement therapy

Rates of adverse vasopressor events

Discussion

Conclusion

Declarations

References

Tables

Additional Declarations

Supplementary Files

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