The impact of blood pressure targets on venous return physiology during post cardiac arrest care

Authors: Simon Schneekloth, Rasmus Paulin Beske, Johannes Grand, Jesper Kjaergaard, Jacob Eifer Møller, Henrik Schmidt, Anders Aneman, Christian Hassager

Abstract

Background

Venous return (VR) physiology may be elucidated using a calculated mean systemic filling pressure analogue (P msa) that reflects the stressed intravascular volume. The aim of this study was to explore differences in VR physiological variables with the hypothesis that vasopressor therapy targeting a higher mean arterial pressure (MAP) would associate with an increased volume state. This would be important to appreciate the intravascular volume effect of an intervention that traditionally is judged by the pressure response alone.

Methods

This exploratory study used data from the BOX trial that investigated a higher (MAP of 77 mmHg, MAP77) versus a lower (63 mmHg, MAP63) blood pressure target during intensive care of survivors from out‐of‐hospital cardiac arrest. Data from 730 patients (MAP63, n = 362 and MAP77, n = 368) were used to calculate P msa, the driving pressure for VR (VRdP, the difference between P msa and central venous pressure [CVP]), the resistance to venous return (RVR, the VRdP divided by the cardiac output [CO]) and heart efficiency (E ~ h ~, the VRdP divided by P msa). Linear mixed models were used to evaluate longitudinal haemodynamic data captured from admission to the intensive care unit and over 36 h.

Results

The P msa was consistently higher in the MAP77 group (p < .03) while the CVP was not statistically different. The greater P msa translated into a progressively increasing VRdP (p < .0001) and thus an increased CO (p < .001). Similar stroke volumes in both groups meant that CO was maintained by an increased heart rate in MAP77 (p < .001). The RVR was higher in MAP77 (p < .04) but gradually decreased in both groups, while the E ~ h ~ was similar overall.

Conclusion

In conclusion, a higher MAP target effectively increased the stressed intravascular volume to sustain a higher CO.

Editorial Comment

This post‐hoc analysis of the BOX trial explores VR physiology and how it is influenced by the use of various doses of noradrenaline and dopamine. A higher blood pressure target appears to increase VR by increasing the stressed intravascular volume. This results in an increase in the CO. These findings are important given the worry about the effect of a higher afterload on cardiac function.

INTRODUCTION

Maintaining an adequate systemic perfusion is essential to sustain organ function after the whole‐body insult of ischemia and reperfusion injury resulting from cardiac arrest and return of spontaneous circulation. Haemodynamic support in the intensive care unit (ICU) is largely focused on mean arterial pressure (MAP) as the major determinant of organ perfusion pressure, with administration of vasopressor(s) the most common intervention along with infusion of fluids. ^1^ Monitoring cardiac output (CO), MAP and central venous pressure (CVP) is often employed to guide therapy, balancing heart pump function, perfusion pressure and intravascular volume.

The heart is often perceived as the primary regulator of CO. There are however no direct physiological feedback pathways or servo control mechanisms that link perfusion of peripheral organs directly to cardiac filling. As a matter of fact, cardiac filling in diastole is a passive process. In contrast to this prevailing cardiocentric view, an alternative histocentric perspective emphasizes the role of the peripheral, metabolically active tissues in the flow of blood back to the heart, that is, the venous return (VR), at the centre of circulatory control. Tissue gas exchange and metabolism include feedback mechanisms that influence regional vascular resistance. Thus, cardiovascular control is exerted by the pressure gradient driving VR and the resistance to VR. The pressure gradient for VR (VRdP) is the difference between the mean systemic filling pressure and the right atrial pressure. The mean systemic filling pressure is generated by the stressed intravascular volume divided by the averaged systemic vascular compliance and provides a numerical descriptor of the volume state within blood vessels at no flow. ^2^ , ^3^ , ^4^ Combining the VR and cardiac function curves as proposed by Guyton ^5^ provides a useful framework unifying the cardiocentric and histocentric views. ^6^ Furthermore, this concept enables the quantitative analysis of the cardiac, volumetric and resistive haemodynamic states.

While VR physiology was recently used to illustrate the cardiovascular state during post‐cardiac arrest care, ^7^ it remains sparsely reported leaving a knowledge gap in understanding the interlinked effects of volume, vasoactive and inotropic therapies. This exploratory post‐hoc study of the large ‘Blood Pressure and OXygenation Targets after Out of Hospital Cardiac Arrest’ (BOX) trial ^8^ aimed to examine the VR physiology in the two different MAP targets investigated in the original study. We hypothesised that targeting a higher MAP would influence the VR differently compared to a lower MAP target, with the main effect relating to the pressure gradient for VR.

MATERIALS AND METHODS

Study design and patients

The original data for the present study were captured in the multicentre, randomized BOX clinical trial (NCT03141099), on which this exploratory post‐hoc study is based. The BOX trial investigated a restrictive PaO2 target (9–10 kPa) vs. a liberal PaO2 target (13–14 kPa) and a MAP of 77 mmHg versus a MAP of 63 mmHg. Furthermore, patients were randomized to undergo device‐based temperature control, with an initial target of 36°C for 24 h, before targeting 37°C for 12 or 48 h. ^9^ , ^10^ In this study, the focus is on the MAP intervention (63 mmHg vs. 77 mmHg) of the BOX trial. The protocol, intervention and primary outcomes of the BOX trial have been published prior to this study, ^8^ , ^9^ , ^10^ , ^11^ including a study on haemodynamic changes during the BOX intervention period of 72 h that reported the MAP, CVP, CO and treatment data that were used in this study. ^12^ In summary, the BOX trial included patients >18 years of age with out‐of‐hospital cardiac arrest (OHCA) of presumed cardiac cause who remained comatose after resuscitation (Glasgow Coma Scale <9). Patients who suffered from OHCA with non‐cardiac aetiology or regained consciousness before admission were excluded. The included patients were randomized in a 1 fashion upon arrival to ICU. This study is reported according to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement ^13^ (checklist in Supporting Information).

Intervention

The intervention was initiated immediately upon randomization. Arterial blood pressure was monitored invasively using a module modified for the BOX trial to offset the displayed blood pressure by 10% in either direction. Thus, by targeting a MAP of 70, two MAP groups of 63 mmHg (MAP63) and 77 mmHg (MAP77) were created while blinding was maintained. The MAP target was achieved by the administration of fluids, norepinephrine and dopamine if other interventions were deemed insufficient, as recommended in the treatment algorithm of the BOX protocol. ^11^

Measurements, data collection and VR physiological variables

All included patients had a pulmonary artery catheter (PAC) inserted immediately after randomization to monitor CVP and CO by thermodilution. The stroke volume (SV) was calculated by dividing the CO by the heart rate (HR). Cardiovascular variables were assessed at 0, 6, 12, 24 and 36 h from PAC insertion.

The mean systemic filling pressure was calculated using the equation proposed by Parkin and Leaning ^14^ that enables an analogue mean systemic filling pressure (P msa) to be obtained in a model of ongoing circulation. ^15^ The derivation of the P msa equation is found in the supplement. The P msa has been validated in human ^16^ , ^17^ , ^18^ and experimental studies ^19^ , ^20^ , ^21^ and used in several previous clinical studies. ^22^ , ^23^ The P msa was calculated Pmsa=CVP•0.96+MAP•0.04+CO•cmmHgThe constants 0.96 and 0.04 reflect the venoarterial partitioning of compliance at a ratio of 25, and the factor c has the dimension of resistance and accounts for the venoarterial compliance ratio and estimated venous resistance adjusted for anthropometric features. ^15^

The VR to the heart is driven by the VRdP established between P msa and the right atrial pressure, using the CVP as a proxy for the latter. When considering the resistance to venous return (RVR), CO is then determined CO=VR=Pmsa–CVP/RVRL/minAn increase in CO might be the result of an increase in P msa, a decrease in CVP, or a decrease in RVR, with either factor in isolation or combination. While the stressed intravascular volume, reflected by P msa, is not directly affected by the operation of the heart, the CVP is more closely linked and will rise in heart failure. The overall pumping efficiency of the heart, E ~ h ~, can be defined by the dimensionless ratio ^24^ :Eh=Pmsa−CVP/Pmsa0≤Eh≤1The E ~ h ~ is close to 1 in normal heart function with CVP approaching 0, while the heart efficiency decreases to 0 in circulatory arrest with equilibration of CVP and P msa.

Ethics

Danish law allows for immediate inclusion of patients who are unable to provide consent if proxy consent is provided by a relative or a medical doctor not affiliated with the trial. Informed consent was obtained from patients who regained consciousness and had sufficiently preserved neurological function.

The original BOX‐trial was approved by Danish authorities through The Danish Regional Committee on Health and Research Ethics (ID: H‐16033436) and Danish Data Protection Agency (ID: RH‐2016‐373) and registered at clinicaltrials.gov (NCT03141099).

Statistical analyses

Baseline data are reported as medians and interquartile ranges (IQR, 25th–75th percentile). Categorical data are reported as counts and percentages. Doses of norepinephrine and dopamine are reported as time‐weighted averages in μg/kg/min, and between‐group differences were assessed by Wilcoxon rank sum test. Distribution of longitudinal haemodynamic data (P msa, VRdP, E ~ h ~, RVR, CO, CVP, SV and HR) was judged by inspection of Q‐Q plots. Data on P msa and E ~ h ~ were skewed and therefore log‐transformed to achieve Gaussian distributions and are reported back‐transformed. Longitudinal haemodynamic data were analysed using linear mixed models which included the intervention and time points as fixed effects. The modelling was conducted using an unstructured covariance pattern to account for the repeated measurements on each participant of the study. Estimated marginal means, including the 95% confidence interval (95% CI) of haemodynamic parameters, are reported.

Pairwise comparisons of physiological variables related to VR between groups (with repeated measurements within subjects) were controlled for multiple testing using the Benjamini‐Hochberg method. An adjusted two‐sided p‐value <.05 was considered statistically significant. All statistical analyses were performed using RStudio version 4.4.2.

RESULTS

The original BOX study included 789 patients, with the sub‐cohort of 730 (92.5%) patients in whom a PAC was inserted reported in this study. Patient and cardiac arrest characteristics at baseline were well balanced between groups and are summarized in Table 1. Both groups (MAP63, n = 362 and MAP77, n = 368) predominantly comprised males (81%) with a median age of 65 years. No interaction was found between MAP targets and the co‐interventions of restrictive or liberal PaO2 targets on P msa, VRdP or HR.

Patients in MAP77 received more fluid (median 6009 [IQR: 4726–7495] mL, compared to MAP63, 5526 [IQR: 4408–6744] mL p < .0001) with an increased diuresis (see Table S1) during the initial 36 h after admission.

In MAP77, 92.9% of patients were treated with norepinephrine and 49.9% of patients were treated with dopamine during the ICU stay. In MAP63, 91.1% of patients were treated with norepinephrine and 40.9% were treated with dopamine during their stay in the ICU. Patients in MAP77 received higher doses of norepinephrine and dopamine consistent with the higher MAP target compared to MAP63 (Table 2).

The intended MAP separation was achieved early after randomization and maintained throughout the study period. The CVP at 0 h was 12 (95% CI 11.2–12.8) and 11.4 (95% CI: 10.5–12.2) mmHg in the MAP77 and MAP63 groups, respectively. At 36 h, the CVP had decreased to 10.6 (95% CI:10–11.3) mmHg in MAP77 and 10.1 (95% CI: 9.4–10.8) in MAP63. The CO was higher in the MAP77 group compared to MAP63 (Figure 1) and sustained by an increased HR, whereas SV was similar in both groups (Table 2). No differences in HR were found between patients treated with and without dopamine in MAP63. Except for 24 h after PAC placement, HR was similar between patients treated with and without dopamine in MAP77 (Tables S2 and S3).

The primary study variables relating to VR are reported in Table 2 at all study time points. The P msa was highest at the time of PAC insertion (0 h) with a subsequent decrease and remained consistently higher in MAP77 compared to MAP63 (Figure 2). The median [95% CI] difference at 0 h was 1.49 (95% CI: 0.57–2.42) and at 6 h 1.13 (95% CI: 0.42–1.85), both p = .003. After 12 h, the median difference was 1.18 (95% CI: 0.44–1.93) and after 24 h 1.09 (95% CI: 0.38–1.80), both p = .003. The difference decreased after 36 h to 0.99 (95% CI: 0.10–1.88) while P msa remained higher in the MAP77.

The higher P msa, but similar CVP, in the MAP77 group compared to MAP63 translated into a consistently higher VRdP that progressively increased in both groups over time (Table 3 and Figure 3). The increase in VRdP corresponded to the increased CO seen in MAP77. Stratifying the included patients by dopamine treatment did not alter the observed results of P msa and VRdP (Figures S1 and S2). The RVR decreased continuously in both groups during the study period while higher in the MAP77 group throughout the study period (Table 3 and Figure 4) Median differences at 0 and 36 h were 0.06 (95% CI: 0.01–0.12) and 0.05 (95% CI: 0.007–0.9), respectively (p = .038 and .036).

In contrast to VRdP and RVR, the E ~ h ~ was overall comparable in both the MAP77 and MAP63 groups, although the groups differed at 6 and 24 h (Table 3). Both groups demonstrated a progressive increase in E ~ h ~ over the study period (Figure 5).

DISCUSSION

This explorative post‐hoc study of data from the BOX trial focused on VR physiology during the initial 36 h of post cardiac arrest care using a higher (77 mmHg) versus a lower (63 mmHg) MAP target. Compared to the MAP63 group, a higher target in the MAP77 group was associated with (1) a greater analogue mean systemic filling pressure reflecting an increase in the stressed intravascular volume; (2) an increased VRdP, and consequently increased CO; (3) a greater resistance to VR; and (4) an overall similar heart efficiency.

The calculation of P msa from MAP, CVP and CO facilitates an interpretation of the haemodynamic state based on VR physiology that extends to the domains of intravascular volume (P msa), cardiac function (E ~ h ~) and vascular resistance (RVR). The P msa has been validated in large animal experiments ^19^ , ^20^ , ^21^ and correlates well with independent measurements in humans. ^16^ , ^17^ , ^18^ Other methods to estimate mean systemic filling pressure based on inspiratory hold manoeuvres ^25^ may be applied in a clinical setting. The P msa algorithm obviates the need for specific interventions and is applicable to non‐intubated patients. It still shows a high level of agreement with incremental airway pressure techniques. ^26^ Furthermore, it is based on commonly measured haemodynamic variables in the ICU, allowing uninterrupted assessment if CO monitoring is continuous. The accurate measurement of CVP is essential given its scaling factor in the P msa equation. The scaling factor for CO reduces its impact on P msa, and in patients without a PAC, bedside echocardiography may be used to monitor CO with acceptable precision. ^27^ The P msa and its derived variables relevant to VR physiology have been increasingly utilised in critically ill and postoperative patients, ^22^ , ^23^ , ^28^ , ^29^ , ^30^ while very few studies have reported the application relevant to post‐resuscitation care from cardiac arrest. ^7^ , ^31^ This post‐hoc study of the BOX trial data is the largest to date reporting P msa and its extended application for interpreting clinical haemodynamic status.

Analogue mean systemic filling pressure, P

msa

The P msa in the linear mixed model showed a U‐shaped progression in both MAP groups during the study period with P msa persistently higher in the MAP77 group. The greater vasopressor dose and fluid volume used to attain MAP77 were associated with an increased P msa and consistent with an increased stressed intravascular volume. Administration of norepinephrine recruits unstressed volume into the stressed circulation by increased arteriolar resistance in predominantly unstressed vascular domains, and venoconstriction of splanchnic capacitance vessels ^32^ , ^33^ as well as splenic contraction. ^34^ Early from the time of randomization, the P msa in both the MAP63 and MAP77 groups was similar or slightly higher than that reported in postoperative cardiac patients, ^23^ in general ICU patients, ^18^ and in patients admitted to ICU in cardiogenic shock. ^22^ The admission P msa was likely influenced by the surge in sympathetic activity triggered by the cardiac arrest as well as by fluids and adrenergic drugs administered during resuscitation, that combined increased the stressed intravascular volume. The underlying pathology triggering the cardiac arrest may also have influenced the initial P msa, for example fluid retention in chronic heart failure. Notably, P msa decreased in the first 6 h in both groups which was plausibly related to a waning sympathetic response as well as commencement of sedation and analgesia in ICU that might reduce vasomotor tone. The P msa remained stable between 6 and 24 h with a trend to increase again towards 36 h. The latter increase may be explained by recovery of vascular tone, including activation of the renin‐angiotensin‐aldosterone system with fluid retention. The separation of P msa between the MAP77 and MAP63 groups contrasts with the findings from a post‐hoc study of the smaller NEUROPROTECT trial in which P msa was numerically greater in the group targeting MAP85‐100 but not statistically significantly different from the groups targeting MAP 65. ^7^ This difference is not surprising given the increased statistical power in the BOX cohort (n = 730) compared to the NEUROPROTECT trial (n = 104).

Driving pressure for venous return

The VRdP increased in both groups over the study period, while clearly separated, with the MAP77 group consistently maintaining a higher VRdP. The increase in VRdP was attributable to the increase in P msa since the CVP did not change significantly, same as data from the NEUROPROTECT post‐hoc study. ^7^ The BOX study protocol explicitly targeted a CVP of 10–15 mmHg, which might explain the lack of differences between MAP groups. It is nevertheless important to note the dispersion in CVP at the different time points as the VRdP is the composite of both P msa and CVP, and minor numerical changes in the individual variables can still translate into a greater change in VRdP. The VRdP in the MAP63 group, and particularly in the MAP77 group, was at the mid‐upper range of the normal gradient of 3–8 mmHg reported in humans. ^16^ , ^35^ , ^36^ The progressive increase in VRdP explains why the CO increased correspondingly over the study period. From a VR physiological perspective, the higher dose of vasopressors used in the MAP77 group effectively acted as a volume intervention, and by increasing the stressed intravascular volume, or decreasing compliance in capacitance vessels, resulted in an increased pressure gradient for the blood flowing back to the heart. In a previous report of BOX haemodynamic data, the SV was not significantly different between the MAP groups (12). Thus, the increase in VRdP did not appear to change the cardiac preload, and the increased CO was achieved by maintaining VR during a more rapid ejection as HR increased in both MAP groups. The chronotropic effects of norepinephrine and dopamine at the doses used in both groups are typically mild. While dopamine has been shown to increase HR in a diverse shock cohort compared to noradrenaline, ^37^ our sensitivity analysis only revealed a non‐significant trend regarding HR. The median dosage of dopamine used in the BOX trial was about 2 μg/kg/min, which is less than the early dosage reported in SOAP II of 14 μg/kg/min associated with increased HR. The cardiovascular receptor profile of dopamine is complex, and at concentrations of less than 5 μg/kg/min, the effect of dopamine is known to primarily decrease vascular resistance to support CO. ^38^ Although dopamine may indeed have a significant chronotropic effect at higher doses, this possible confounding effect is not expected in all patients treated with dopamine in the BOX trial, and is not supported by the sensitivity analyses (Tables S2 and S3).

Resistance to venous return

The RVR successively decreased in both groups over time, although the MAP77 group always maintained a greater RVR compared to the MAP63 group. The balance between increased VRdP versus any increase in RVR by norepinephrine will determine the overall effect on CO. In this study, increased vasomotor tone by norepinephrine expanded the effective circulating volume as evidenced by greater P msa and VRdP, and while MAP77 had a higher RVR it was still not sufficient to offset the increase in return blood flow generated by a greater VRdP. The decrease in RVR observed in both groups over time was comparable to a previous report investigating VR physiology during post‐cardiac arrest care in ICU (6). The cause for the reduction in RVR was likely multifactorial and might have involved a subsiding surge in sympathetic nervous activity following cardiac arrest and vasodilation from initiating sedatives and analgesics in ICU. Endothelial dysfunction following systemic ischaemia–reperfusion injury could also promote vasodilation from systemic inflammatory activation as part of the post‐cardiac arrest syndrome. ^39^ , ^40^

Heart efficiency, E

~ h ~

The E ~ h ~ remained overall similar between the MAP77 and MAP63 groups, with an increase over time observed in both. The increased afterload in MAP77 was hence, based on E ~ h ~, not associated with any adverse effect on cardiac function compared to MAP63. Furthermore, the observed increase in CO was associated with increased VRdP, but not with a difference in the intrinsic cardiac pump function. The early E ~ h ~ was quite severely reduced, as might be expected after cardiac arrest, but improved over time to values comparable with patients admitted to ICU with acute circulatory failure (17) following cardiac surgery (18). The E ~ h ~ increased continuously during the study period in both groups, with a slightly faster trend in MAP77, consistent with recovery from myocardial stunning following cardiac arrest. ^41^ , ^42^

This study has several important strengths and limitations. The large sample size is conducive to robust comparisons between the MAP77 and MAP63 groups. All patients were uniformly monitored using a PAC that reduced device‐related variability in CO and CVP measurements. While CVP was sampled in a standardized manner in accordance with local and accepted protocol, no direct corrections regarding the respiratory cycle were made. The MAP targets were achieved using protocolized interventions while the treating team remained blinded. The design of this post‐hoc exploratory study means that associations between the protocolized MAP77 and MAP63 targets and variables related to VR physiology could be identified, but no causal inferences can be made. The results should be viewed as hypothesis generating, and the external validity to other clinical conditions with acute, severe circulatory failure needs to be established in further studies.

In conclusion, in this exploratory post‐hoc study of data from the BOX‐study, an increase in the analogue mean systemic filling pressure (P msa) was observed, associated with the higher MAP target of 77 mmHg. The increase in P msa translated into a higher VRdP that aligned with an increase in CO. The RVR continuously decreased, while higher in the MAP77 group, and may thus have further facilitated the VR and a related increased CO. In contrast, the cardiac pump function as estimated by heart efficiency (E ~ h ~) was not statistically different between the MAP77 and MAP63 groups. The description of VR physiology using variables obtained without further interventions during ongoing post‐cardiac arrest care warrants further study. These studies should focus on clarifying the interactions between the intravascular volume, cardiac pump function and vascular resistance states to optimize haemodynamic support.

AUTHOR CONTRIBUTIONS

All authors revised the manuscript and approved the final product before submission. AA, SS, RPB and CH wrote the initial draft. AA conceptualized the study. Data curation and interpretation was done by AA, SS, RPB, CH, JK, JG and JEM. The original steering committee of the BOX trial was CH, JK, JEM and HS.

CONFLICT OF INTEREST STATEMENT

The authors have no potential conflicts of interest to disclose.

Supporting information