Discussion
The present study shows that the average NRR during the first night following hospital admission provides powerful prognostic information regarding intrahospital mortality in all-comers with ACS presenting in the emergency department. The prognostic value is independent from established risk predictors such as the GRACE score and LVEF. In addition, the NRR significantly improved the GRACE risk model. Regarding 2-year mortality, NRR also proved to be an independent risk factor but only improved the GRACE risk model to a weaker extent.
Current guidelines recommend monitoring of patients with ACS as these patients are at substantial risk of death due to malignant arrhythmias, reinfarction or progressive heart failure.14 Some patients, however, are likely to benefit from an intensified treatment and monitoring. The identification of high-risk patients at an early stage after admission would be of great clinical interest. Established methods for risk assessment in patients with ACS are clinical risk scores such as the GRACE score or LVEF.1 2 15 However, prognostic evaluation using these approaches has limitations and risk markers complementary to the established methods are warranted. The optimal risk marker would be easily and quickly determinable, inexpensive, without demands on technical equipment or on patient cooperation.16 Most of these requirements apply to the NRR: the determination of NRR can be carried out using most surveillance monitors and without additional expense. The nocturnal determination off NRR allows standardised test conditions, also without any extra effort and without specific patient cooperation.
The NRR can be assessed by different methods through routine surveillance monitors. In this study, the respiratory rate was calculated from the ECG channel because not all surveillance monitors support other methods of respiration rate assessment.12 This method is therefore applicable to monitoring stations with basic technical equipment. Since all patients with ACS require monitoring especially in the first 24–48 hours,14 the determination of NRR could be integrated into routine clinical practice without significant additional expense.
We were able to show that the average NRR during the first night after admission provides additional prognostic information, especially with respect to the intrahospital mortality. On the long term, the NRR might therefore be helpful for clinical decisions such as prolonged monitoring and intensified medical, interventional and device-based treatment of high-risk patients with ACS.
Since the time of revascularisation can have a considerable effect on NRR and on outcome, we have carried out subgroup analyses of patients who underwent PCI before NRR assessment, patients who underwent PCI after NRR assessment and patients who did not undergo PCI. A significantly higher NRR can be seen in the non-survivors of all subgroups except for patients without PCI with regard to 2-year mortality. A very good C-statistic was found for patients in whom the NRR was assessed prior to revascularisation with regard to intrahospital mortality. These patients might have benefited from an earlier invasive diagnosis and therapy. However, the low event rate in this subgroup only allows to draw this conclusion to a limited extent.
The fact that the respiratory rate provides prognostic information in postinfarction patients has already been shown in other studies.5 17 18 The NRR seems to be particularly suitable because of its assessment under standardised conditions in the night compared with daytime measurements.6 Other studies used standard 24-hour Holter recordings or short records of 10 min respiratory rate at rest within an extended period for prediction of mortality after myocardial infarction.5 6 17 The difference of our study is first that we have determined the NRR in the routine clinical setting of the emergency department via standard patient monitors without any additional diagnostic tools. Second, the time of NRR assessment is clearly defined in our study, that is, the first night after hospital admission. Thus, by the presented setting objective prognostic information can be obtained shortly after the clinical event, which can be useful in addition to other risk factors for immediate planning of further treatment of the individual patient. Third, other studies have assessed an association between respiratory rate and post-MI prognosis. We have focused on a broader spectrum of all-comers with ACS including patients with UAP.
The respiratory rate is strongly influenced by the balance of the autonomic nervous system. Increased respiratory rate at admission may therefore by a sign of altered autonomic control of respiratory activity due to enhanced sympathetic activity and vagal withdrawal in ACS and also maybe due to progressive pulmonary congestion.4 Other parameters evaluating the function of the autonomic nervous system, such as various parameters of heart rate variability, are also strong risk predictors in patients with ACS.4 19–22 For assessment of these parameters, however, the presence of sinus rhythm is mandatory which is not needed for determination of NRR.
The limitations of our study need to be recognised. First, we cannot compare the prognostic information of NRR with parameters of heart rate variability since the study cohort includes patients with atrial fibrillation. However, as atrial fibrillation in patients with ACS is often prevalent, risk stratification by NRR which can be performed irrespective of the patient’s heart rhythm is favourable. Second, the presence of motion artefacts and other technical failures could affect the determination of the respiratory rate from the ECG channel. Further underlying respiratory pattern could affect the NRR. The calculation of the average respiratory rate over a period of 6 hours, however, should reduce the influence of corresponding disturbances. The choice of the period from 0:00 to 6:00 was due to the consideration that during this time the patient is most likely asleep; however, there was no monitoring of the sleep state. However, we consider that the chosen nightly episode is the optimal time for the standardised determination of the respiratory rate since the external influences are the lowest at this time. We also calculated the NRR from shorter recording intervals (1 and 2 hours). Again, there were highly significant differences with respect to both endpoints. However, the respective C-statistic was better with a longer recording time (6 hours). We interpret this by the fact that disturbances have less effects with longer recording time. In addition, specific respiratory disorders that may affect the results are also better detected with longer recording time.
Third, the selected cut-off for NRR of 16.8/min was determined retrospectively and was not derived from pathophysiological reasoning or previous literature data. Fourth, ACS is composed of multiple types of infarction and ischaemia which have variable effects on heart and vascular baroceptors and chemoceptors and finally also on the NRR. However, we performed subgroup analyses on patients with STEMI, NSTEMI and UAP and non-survivors of all ACS subsets presented with significantly higher NRR values except patients with UAP who died within 2 years. Fifth, we cannot provide systematic information about the exact time of the onset of ACS and with regard to drugs given in the first hours of ACS which both may have an effect on NRR. Sixth, LVEF was assessed by echocardiography or by left ventriculography. However, studies report a sufficient correlation of both modalities to assess LVEF.23
Finally, further studies are needed to show that incorporation of the NRR into the risk stratification of patients with ACS and clinical decision-making contributes to an improved prognosis.