Targeted mild hypercapnia after out-of-hospital cardiac arrest is associated with favourable cardiovascular effects. A sub-study of the TAME cardiac arrest trial.

doi:10.21203/rs.3.rs-3085980/v1

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Targeted mild hypercapnia after out-of-hospital cardiac arrest is associated with favourable cardiovascular effects. A sub-study of the TAME cardiac arrest trial.

https://doi.org/10.21203/rs.3.rs-3085980/v1

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Purpose:

Hypercapnic acidosis may elicit detrimental haemodynamic effects in critically ill patients. We aimed to investigate the consequences of targeted mild hypercapnia (TMH) versus targeted normocapnia (TN) on pulmonary vascular resistance and right ventricular function in patients

resuscitated from out-of-hospital cardiac arrest (OHCA).

Methods:

Single-centre, prospective, sub-study of the Targeted Therapeutic Mild Hypercapnia After

Resuscitated Cardiac Arrest (TAME) trial. Patients were randomised to TMH (PaCO₂= 6.7–7.3 kPa) or TN (PaCO₂= 4.7-6.0 kPa) for 24 hours. Haemodynamic assessment was performed with right heart catheterisation and serial blood-gas analyses every 4th hour for 48 hours.

Results:

We studied 84 patients. Mean pH was 7.24 (95 % CI 7.22–7.30) and 7.32 (95 % CI 7.31–7.34) with TMH and TN, respectively (P-group < 0.001). Pulmonary vascular resistance index (PVRI), pulmonary artery pulsatility index, and right atrial pressure did not differ between groups (P-group > 0.05). Mean cardiac index was higher with TMH (P-group < 0.001): 2.0 (95 % CI 1.85–2.1) vs 1.6 (95 % CI 1.52–1.76) L/min/m². Systemic vascular resistance index was 2579 dyne-sec/cm-5/ m² (95 % CI 2356–2830) with TMH, and 3249 dyne-sec/cm-5/ m² (95 % CI 2930 – 3368) with TN (P-group < 0.001). Stroke volumes (P-group = 0.013) and mixed venous oxygen saturation (P-group < 0.001) were higher in the TMH-group.

Conclusion:

In resuscitated OHCA patients, targeting mild hypercapnia did not increase PVRI or worsen right ventricular function compared to TN. TMH comparatively improved cardiac performance and mixed venous oxygen saturation.

Trial registration number: NCT03114033

Out-of-hospital cardiac arrest

targeted mild hypercapnia

right heart catheterisation

post-cardiac arrest care

hypercapnic acidosis

In this single-centre, prospective sub-study of a large, randomised cardiac arrest trial targeted mild hypercapnia was not associated with increased pulmonary vascular resistance or signs of right ventricular failure. Compared to targeted normocapnia, mild hypercapnia improved cardiac performance and mixed venous oxygen saturation, suggesting favourable cardiovascular effects.

Myocardial dysfunction is prevalent in adults admitted to hospital following resuscitation after out-of-hospital cardiac arrest (OHCA), and cardiovascular failure is a major contributor to early mortality in these patients [1–3]. The haemodynamic profile of resuscitated cardiac arrest patients is typically characterised by reduced cardiac output, hypotension, and disturbed vasomotor regulation [1, 4, 5]. European guidelines for post-resuscitation care highlight the importance of optimising haemodynamics after cardiac arrest [6].

The Targeted Therapeutic Mild Hypercapnia After Resuscitated Cardiac Arrest (TAME) trial [7] investigated whether targeting mild hypercapnia (TMH [PaCO₂ = 6.7–7.3 kPa]) compared to targeting normocapnia (TN [PaCO₂ = 4.7-6.0 kPa]) for 24 hours in comatose adults resuscitated after OHCA could improve neurological outcomes at six months. In this regard, hypercapnia increases cerebral blood flow [8], but hypercapnic acidosis is also believed to exert significant systemic haemodynamic effects [8–10]. Such putative effects include impaired myocardial contractility, systemic vasodilation, improved systemic oxygenation and increased pulmonary vascular resistance (PVR). Our current understanding of the cardiovascular effects of hypercapnic acidosis, however, is primarily based on pre-clinical and animal studies [9, 11]. Thus, the haemodynamic consequences for comatose adults resuscitated after OHCA are unclear.

Prior to the TAME trial, there was concern that hypercapnic acidosis would increase pulmonary vascular resistance, right ventricular afterload and exacerbate right ventricular failure [12–14]. This, in turn, could increase systemic venous congestion and worsen renal function [15]. If induced, these adverse haemodynamic effects could have significant consequences as right ventricular dysfunction after cardiac arrest is both common and associated with worse outcomes [16, 17].

We hypothesised that TMH compared with TN for the first 24 hours after OHCA would increase PVR, exacerbate right ventricular dysfunction, and adversely alter the systemic circulation. To test this hypothesis, we compared pulmonary vascular resistance index (PVRI); pulmonary artery pulsatility index (PAPI) and right atrial pressure (RAP); Cardiac index (CI) and cardiac power output (CPO) and systemic vascular resistance index (SVRI) and fluid balance in patients randomised to either TMH or TN within the TAME trial.

Trial design and patients

The study was a prospective sub-study of patients enrolled in the TAME trial at Oslo University Hospital. Patients were randomised in a 1:1 ratio to TMH (PaCO₂ = 6.7–7.3 kPa) or TN (PaCO₂ = 4.7-6.0 kPa) for a 24-hour period beginning at randomisation. Hospitalised comatose adults (18 years or older) resuscitated from OHCA of a presumed cardiac cause with sustained return of spontaneous circulation (ROSC) for 20 minutes, were eligible for enrolment. Full eligibility criteria are detailed in the main trial manuscript [7]. Haemodynamically unstable patients and those deemed to be in cardiogenic shock were not excluded.

Prehospital data were systematically collected according to the Utstein Guidelines [18]. The TAME trial and the sub-study were approved by the regional ethics committee (NCT03114033, REK 2018/386). Patients were initially included and randomised without consent. Written informed consent was obtained from patients’ next of kin in all cases and from patients regaining consciousness after cardiac arrest.

Emergency coronary angiography and coronary intervention, defined as prior to or immediately after ICU admission, was performed in all patients presenting with ST-segment elevation or at the discretion of the treating physician. Haemodynamic information from right heart catheterisation were available for treatment decisions that were made at the discretion of the treating physician.

Post-cardiac arrest care

All patients were sedated, intubated, and mechanically ventilated during the intervention period. A target Richmond Agitation-Sedation Scale score [19] of -4 (scale range − 5 (unarousable) to + 4 (combative)) was achieved by titrating propofol in combination with fentanyl. Propofol was replaced with midazolam, if needed, in haemodynamically unstable patients. Neuromuscular blockade was administered if needed. Active cooling with a surface cooling device (Arctic Sun™, BD, Franklin, NJ) was initiated immediately after ICU admission with targeted temperature management (TTM) set to 33°C (TTM 33) for the initial 24 hours after cardiac arrest. This was followed by gradual re-warming by 0.5°C/hour, and fever control for an additional 48 hours.

Arterial blood gas (ABG) measurements were used to guide the respiratory rate adjustments of minute ventilation to optimise time in the target PaCO₂ range. For patients allocated to TMH, in the event of severe metabolic acidosis (pH < 7.1 and base excess < − 6 mmol/L), the initiation of the TMH protocol was to commence after correction of the acidosis. Respiratory acidosis was not corrected with buffer solutions. Return to normocapnia after TMH was conducted over a minimum of four hours.

Crystalloid fluids were administered initially in all patients to optimise right ventricular filling pressures. Urine output was targeted at > 1.0 mL/kg per hour. Vasopressors and inotropes (primarily norepinephrine and dobutamine) were used, if needed, to achieve adequate organ perfusion and a target mean arterial pressure (MAP) of > 65 mmHg.

Haemodynamic Measurements

Advanced haemodynamic monitoring was obtained by ultrasound-guided insertion of a 7.5 F triple lumen balloon-tipped catheter into the pulmonary artery (Swan Ganz, Edwards Lifesciences, Irvine, CA). The first haemodynamic measurements were obtained four hours after randomisation, and the start of TMH or TN. All measurements were performed with the patient in a supine position. Systolic, diastolic and mean pulmonary artery pressures (sPAP, dPAP and mPAP) were obtained from the distal port. Right atrial pressure (RAP) was obtained from the proximal port. Systemic mean arterial pressure (MAP) was acquired from a radial arterial line. Cardiac output (CO) and index (CI) were obtained through a thermodilution technique with bolus infusions of 10 ml of cold 5% glucose. The average of 3 measurements with less than 10% variance was sampled. Pulmonary capillary wedge pressure (PCWP) was measured with the catheter balloon inflated in wedge position and registered at end-expiration. Central mixed venous blood samples were drawn from the distal port of the pulmonary artery catheter and time-matched with arterial blood samples drawn from the radial arterial line. Indexed systemic (SVRI) and pulmonary (PVRI) vascular resistance were calculated by the following equations: SVRI= (MAP- RAP) *80/CI and PVRI=(mPAP-PCWP) *80/CI. Cardiac power output (CPO) was calculated using the formula; CO*MAP*0.0022. Pulmonary artery pulsative index (PAPi) was estimated as (sPAP-dPAP/RAP).

Haemodynamic measurements, ventilator settings and arterial and mixed venous blood samples were taken every fourth hour after insertion of the pulmonary artery catheter in a time matched manner throughout the 48 hours study period. The doses of relevant administered drugs and intravenous fluids were time-matched with PAC measurements, and included propofol, fentanyl, midazolam, dobutamine and norepinephrine. Intravenous fluids and urine output were recorded every 4 hours.

Statistical analysis

Differences between baseline variables and rates of coronary pathologies were compared using Student t test, χ² test, and Wilcoxon rank-sum test, as appropriate. Baseline variables are presented as mean ± SD or proportions (%), and for variables with a non-normal distribution, data are presented as median and lower to upper quartile (Q1–Q3).

Between-group differences for the continuous haemodynamic and metabolic variables in the intervention period (24 hours) were evaluated with repeated-measures mixed models with a heterogenous first-order autoregressive covariance structure with treatment-group, time, and the interaction term of treatment group with time (if significant) as fixed effects. Ventilator settings and doses of administered drugs and fluids were evaluated in the same fashion. Models were fitted using the restricted maximum likelihood (REML) method. Overall differences between treatment groups are reported as β-coefficients (estimate of treatment effect) and P - values, denoted as P-group. Model estimated marginal means (EM) for the entire intervention period are reported with 95% confidence intervals. Dependent variables with a non-normal distribution of the residuals were log-transformed to improve the model fit. β-coefficients of the log-transformed variables (i.e., stroke volume) are reported as percentage (%) difference. Tests were 2-sided, and statistical significance was defined as P < 0.05. Statistical analysis was performed using IBM SPSS (Version 28.0. Armonk, NY: IBM Corp) and R (R Core Team (2013). Version 2022.12.0 + 353. R Foundation for Statistical Computing, Vienna, Austria.). Graphs were made using R and the GGplot2 package.

Patient population

Between January 2019 and August 2021, 84 out of 137 patients enrolled in the TAME trial received a PAC and were eligible for the present sub-study. Of these, 41 and 43 patients were randomised to TMH and TN, respectively. See consort diagram (Electronic supplementary material (ESM), Fig. S1).

There were no statistically significant differences in the baseline characteristics between the treatment groups (Table 1). Emergency coronary angiography was performed in all patients prior to ICU admission. Distribution of coronary pathologies and success-rates of PCI did not differ between the two groups (ESM, Table S1). Six-month survival was 76% in the TMH-group versus 65% in the TN-group (P = 0.416).

Intervention

Both groups achieved the desired levels of PaCO₂ (Fig. 1A, Table 2) within 4 hours and during the intervention period (P-group < 0.001). Mild hypercapnic acidosis (Fig. 1B, Table 2) was present in the TMH-group (P-group < 0.001). PaO₂/FiO₂-ratio (Fig. 1C, Table 2) did not differ significantly between groups (P-group = 0.601), and the estimated mean temperatures (Table 2) were similar during the intervention (P-group = 0.258).

Haemodynamic measurements

The first set of hemodynamic data was obtained at the earliest possible time during the first four hours after randomisation. Compared to the normal range, PVRI was considerably elevated in both treatment groups after ICU-admission, and gradually declined during the observation period (Fig. 2A). PVRI (Fig. 2A, Table 2) was not significantly different in the TMH-group compared to the TN-group (P-group = 0.211). Mean pulmonary artery pressure (Fig. 2B, Table 2) was slightly higher in the TMH-group (P-group = 0.006). RAP (Fig. 2C, Table 2) and the haemodynamic parameter of right ventricular function, PAPi (Fig. 2D, Table 2), was similar in the treatment groups (P-group = 0.315 and P-group = 0.379, respectively)

Overall, the parameters of cardiac function represented by cardiac index, stroke volume, and cardiac power output (CPO) were impaired in the initial post-resuscitation phase and improved gradually over time (Fig. 3A, B and C). The TMH-group had a significantly higher cardiac index (Fig. 3A, Table 2) compared to the TN-group (P-group < 0.001). This was mainly due to higher stroke volumes (Fig. 3B, Table 2) in the TMH-group (P-group = 0.013). The heart rate (Table 2) did not differ significantly (P-group = 0.179). CPO (Fig. 3C, Table 2) was significantly higher in the TMH-group compared to the TN-group (P-group = 0.003)

SVRI (Fig. 3D, Table 2) was comparatively lower in the TMH-group (P-group < 0.001). MAP (Table 2); however, it was not significantly different between groups (P-group = 0.177). PCWP (Table 2) was similar (P-group = 0.727). Mixed venous oxygen saturation (MVO2, Fig. 3E, Table 2) was higher in the TMH-group (P-group < 0.001). Lactate (Table 2) did not differ significantly (P-group = 0.202).

Positive fluid balance (Fig. 3F, Table 2) was comparatively lower in the TMH-group (P-group = 0.028, and there was a significant overall interaction between treatment-group and time; p-value = 0.037), with an estimated mean positive fluid balance over 24 hours at 3369 mL (95% CI 2779–3396) versus 4083 mL (95% CI 3507–4658) in the TN-group. Total urine output (Table 2) was not significantly different over the observation period (P-group = 0.290).

Sedation and vasoactive medication

The groups received similar amounts of sedatives during the intervention: Propofol (P-group = 0.984 [β = 0.01 mg/kg/hour, 95% CI -0.61 to 0.62].), fentanyl (P-group = 0.349 [β = 0.18 mcg/kg/hour, 95% CI -0.20 to 0.57].) and midazolam (P-group = 0.655 [β = 0.01 mg/kg/hour, 95% CI − 0.80 to 0.05].). Patients in the TMH-group were on average treated with slightly higher doses of norepinephrine than the TN-group (P-group = 0.026 [β = 0.06 mcg/kg/minute, 95% CI 0.008–0.11].). Dobutamine use did not differ significantly between the groups (P-group = 0.835 [β = − 0.08 mcg/kg/min, 95% CI – 0.87 to 0.70].).

Compared to targeted normocapnia, targeted mild hypercapnia after OHCA was associated with mild hypercapnic acidosis and no increase in pulmonary vascular resistance. We found no signs of worsened right ventricular function, as expressed by right atrial pressure and pulmonary artery pulsatility index. TMH increased cardiac index and power output, lowered systemic vascular resistance and curbed positive fluid balance.

To the best of our knowledge, this is the first study to prospectively explore the haemodynamic effects of TMH in a cohort of patients from a large randomised cardiac arrest trial population. Our results indicate that targeting mild hypercapnia after OHCA was associated with beneficial cardiovascular effects, and that potential adverse haemodynamic effects on right sided cardiac function and haemodynamics in general were not observed. Accordingly, our main concern prior to study initiation was refuted. This may have important clinical implications because a significant increase in right ventricular afterload can precipitate right ventricular failure, especially in patients with compromised right ventricular function [9, 11, 13, 16].

The cardiac index was likely elevated by TMH due to increased stroke volumes and lowering of the systemic vascular resistance. Cardiac power output, a measure of cardiac pumping ability [20], was also significantly higher in the TMH-group and suggests improved cardiac function. CPO is strongly correlated to outcomes across a broad spectrum of acute cardiac diseases, including cardiac arrest [20–22]. Hypercapnic acidosis directly inhibits cardiac and vascular muscle contractility in isolated hearts [10, 11], but these effects may be counterbalanced by a positive inotropic pathway involving the central and peripheral chemoreceptors and the sympathoadrenal system [9, 10]. In addition, hypercapnic acidosis has a direct vasodilatory effect on both the coronary and systemic vessels, and several studies have shown that venous return may be increased [10, 14, 23, 24]. The TMH-group received less fluids during the intervention and had a lower positive fluid balance after 24 and 48 hours. This might be due to improved cardiac output and decreased need for preload support.

The increased mixed venous oxygen saturation in the TMH-group likely reflects both improved oxygen delivery with higher cardiac output and improved peripheral tissue oxygenation [25, 26]. Hypercapnia improves oxygen unloading into tissues by decreasing haemoglobin oxygen affinity [8, 27], and has been shown to cause microvascular vasodilation, which promotes tissue perfusion [28]. Lactate was numerically lower for the TMH-group, but the difference was not statistically significant. Hypercapnia may reduce cellular respiration and oxygen consumption [29], which could theoretically also increase the MVO2.

TMH causes respiratory acidosis, and the cardiovascular consequences observed in this trial is likely caused by hypercapnic acidosis [8]. The haemodynamic effects of TMH were apparent at the first right heart catheterisation and dissipated soon after reversal. This confers a fast acting and quickly reversible effect. Importantly, the effect was sustained during treatment. The slightly higher doses of norepinephrine administered in the TMH-group may be due to systemic vasodilation and/or impaired catecholamine sensitivity caused by acidosis [30].

Beyond the situation of post-cardiac arrest management, hypercapnia and hypercapnic acidosis are common in critically ill patients [31, 32]. Our investigation may add clinical knowledge relevant to other conditions where hypercapnia is relatively frequent (e.g., acute respiratory distress syndrome), and where there is no randomised controlled evidence of its physiological effects [13, 30]. In this regard, cardiac arrest is frequently followed by pulmonary complications and a significant number of resuscitated OHCA patients eventually fulfil the criteria for acute respiratory distress syndrome [31]. Myocardial dysfunction and congestion likely play a significant role in impaired gas exchange and lung damage after cardiac arrest, but their significance remains unclear [29, 30]. Lung protective ventilation has become standard post-ROSC care [30], but there is insufficient evidence to advise for or against mild hypercapnia [6]. Balancing ventilation targets against the potentially detrimental haemodynamic effects have been a concern [30]. Our study is currently the largest randomised study to demonstrate that mild hypercapnia is not associated with adverse cardiovascular effects. In contrast, we observed that mild hypercapnia was associated with improved cardiac performance, increased oxygen delivery, and a curbed positive fluid balance.

This single centre study has important strengths and limitations. The post-arrest management in this study was homogeneous, the hemodynamic monitoring granular, and data collection rigorous, strengthening the confidence in our observations. On the other hand, the limited number of patients may represent a select population. There were higher proportions of shockable rhythms and male sex patients compared with the general OHCA population. Furthermore, the haemodynamic effects demonstrated in comatose adults resuscitated after OHCA may not be extrapolated to a more general intensive care population. TTM at 33 degrees centigrade is associated with a significant increase in systemic and pulmonary vascular resistance, and cardiac output is frequently decreased [33]. This may influence the effect of TMH. Lactate levels are typically mildly elevated as compared with 36°C [33].

In comatose adults resuscitated after out-of-hospital cardiac arrest, targeted mild hypercapnia, compared to targeted normocapnia, was not associated with increased pulmonary vascular resistance, indices of right ventricular failure or adverse hemodynamic effects. Overall, the improved cardiac performance was observed in patients allocated to targeted mild hypercapnia indicates favourable cardiovascular effects.

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Conflicts of interest: Olasveengen is a board member of the Laerdal Foundation, none of the other authors have any conflicts of interest to disclose.

Acknowledgements: We thank all involved in the TAME trial without this study would not be possible. We also thank the Department of Research and Development, Acute Care Division and Department of Cardiology, Oslo University Hospital for all their good will and support in providing necessary infrastructure. We specifically thank Tomas Drægni, Siw Pedersen Trudvang, Knut Ove Pettersen, Petra Olsson, Margit Kjuus and Lillian Rassmussen for all their assistance with patient and study follow-up.

Funding source: This study was funded by National Health and Medical Research Council of Australia, the Health Research Board of Ireland, and the Health Research Council of New Zealand, and the Southern and Eastern Norway Regional Health Authority. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Table 1 and 2 are available in the Supplementary Files section.

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Targeted mild hypercapnia after out-of-hospital cardiac arrest is associated with favourable cardiovascular effects. A sub-study of the TAME cardiac arrest trial.

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Abstract

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Take-home-message

Introduction

Methods

Trial design and patients

Post-cardiac arrest care

Haemodynamic Measurements

Statistical analysis

Results

Patient population

Intervention

Haemodynamic measurements

Sedation and vasoactive medication

Discussion

Conclusions

Declarations

References

Tables

Supplementary Files

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