INTRODUCTION
Resuscitation quality is improving through the use of updated guidelines including the “chain of survival concept” [1–3]. However, the percentage of favorable neurological outcomes, defined as the ability to return to daily life after an out-of-hospital cardiac arrest (OHCA) remains low [4–8]. The effectiveness of post-resuscitation care including targeted temperature management has resulted in improved neurological outcomes [9–13], but improved outcomes after return of spontaneous circulation (ROSC) require significant effort [14]. Identifying associations between favorable neurological outcomes and clinical factors is challenging, but these associations are crucial for guiding the effective use of limited critical care resources and optimizing patient outcomes [15].
Current guidelines recommend delaying evaluations of neurological outcome until 72 hours after ROSC [16]. However, patients’ families and healthcare providers often seek neurological prognoses sooner than that [17]. Several laboratory parameters measured at hospital arrival, such as serum potassium and sodium levels, have been evaluated for prognostic value after OHCA [18,19]. Higher serum potassium levels were significantly associated with poor neurological outcomes in a concentration-dependent manner [18]. Both hyponatremia and hypernatremia at hospital arrival were also associated with a lower likelihood of favorable neurological outcomes [19]. However, the most appropriate laboratory parameters at hospital arrival for development of patient prognosis after OHCA have not been identified. Serum lactate level is a biomarker reflecting the acute phase in patients, and serum albumin levels reflect chronic illness and nutritional status. Serum lactate to albumin ratios are better predictors
of favorable neurological outcomes in critically ill patients than serum lactate or albumin level values alone [20–23]. Specifically, a positive correlation with mortality was reported for patients with high serum lactate to albumin ratios [20,24]. However, no studies have investigated the association between lower serum lactate to albumin ratios, as categorized into quartiles, and favorable neurological outcomes in patients with OHCA.
We evaluated the possibility of an association between lower serum lactate to albumin ratio quartile and favorable neurological outcomes in patients with OHCA.
METHODS
Ethics statement
This study was approved by the Clinical Research Institutional Review Board of Dokkyo Medical University Saitama Medical Center (No. 22043). The study’s registry protocol complied with the Declaration of Helsinki and ethical guidelines of each hospital. Individual informed consent was waived by the Act on the Protection of Personal Information and the Ethical Guidelines for Medical and Health Research Involving Human Subjects of Japan. Data were de-identified by each fire department before analysis.
Study design and setting
This retrospective observational study was conducted using the Japanese Association for Acute Medicine–Out-of-Hospital Cardiac Arrest (JAAM-OHCA) Registry, a nationwide multicenter and prospective OHCA database. This registry collects both pre- and in-hospital data on resuscitation of patients with OHCA arrival at emergency departments in Japan [25–27]. The profile of the registry was previously described [25].
Prehospital data were uniformly collected according to the Utstein style international guidelines for reporting OHCAs [28]. The recorded data include the regional location (prefecture) of cardiac arrest, emergency medical services (EMS) timeline including total care time, bystander witness status, bystander cardiopulmonary resuscitation (CPR) status, telephone dispatcher CPR guidance details, year of occurrence of OHCA, first documented on-scene cardiac rhythm, receipt of prehospital adrenaline status, performance of prehospital advanced airway management, and neurological outcomes. The emergency dispatch center records time data for EMS performance, including those of the initial emergency, arrival at the scene of the cardiac arrest, contact with the patient, and hospital arrival [29]. The Japanese Fire and Disaster Management Agency (FDMA) verified prehospital data electronically uploaded to the FDMA registry system database. Incomplete uploaded data forms were returned by the FDMA for completion by the respective fire stations.
Using a standardized online form, clinicians or clinical data managers at each hospital documented in-hospital data, including age, sex, etiology of the cardiac arrest, laboratory data, and neurological outcomes. Freedom from logical contradictions was then determined for each patient. The cerebral performance category (CPC) scale was used to evaluate neurological status: CPC 1, favorable cerebral performance; CPC 2, moderate cerebral disability; CPC 3, severe cerebral disability; CPC 4, coma or vegetative state; and CPC 5, death [28]. Finally, the JAAM-OHCA Registry Committee consisting of experts in emergency medicine and clinical epidemiology confirmed the data. Incomplete data sheets were sent by a committee member to participating institutions for completion when possible.
Study population
The registry used in this study included all patients diagnosed with OHCA in Japan between June 1, 2014, and December 31, 2021. The exclusion criteria were as follows: (1) no resuscitation at the hospital; (2) nonmedical cardiac arrest etiology; (3) age <18 years; (4) treatment with extracorporeal membrane oxygenation; (5) no ROSC achieved; (6) not hospitalized; and (7) time from emergency call to laboratory data measurement >120 minutes. Nonmedical etiologies were defined as trauma, drowning, poisoning, burns, asphyxia, and hanging [26]. Patients with missing essential data were excluded from the analysis.
EMS system in Japan
Details of the Japanese EMS system were previously described [26]. In response to an emergency call, the nearest fire station dispatches an ambulance. Telephonic emergency calls are responded to 24 hours daily. The most highly trained prehospital nonphysician emergency care providers, designated as emergency life-saving technicians (ELSTs), are allowed to insert intravenous lines for OHCA patients; specially trained ELSTs are allowed to perform protocolized tracheal intubation and administer intravenous adrenaline. Most ambulances have three emergency providers including at least one ELST. CPR is conducted according to Japanese CPR guidelines [26]. Because prehospital resuscitation by EMS personnel cannot be terminated according to Japanese law, nearly all OHCA patients are transported to hospitals [27].
The absence of signs of circulation and cardiac mechanical activity indicate cardiac arrest. This is recorded by a medical professional; the recorded findings include respiratory motion, breathing assessment, carotid artery pulsation, and three-lead electrocardiogram findings [30]. Causes of arrests are determined clinically by physicians deployed with EMS personnel [30].
Outcome measurements
A CPC 1 or 2 classification was the primary outcome that indicated 30-day survival with favorable neurological outcome. The secondary outcome was 30-day survival after OHCA.
Statistical analysis
Categorical variables are expressed as frequencies and percentages, and continuous variables are reported using means and standard deviations unless otherwise specified. When appropriate, medians and interquartile ranges were used to describe continuous variables. Analysis of variance or the Kruskal-Wallis test was used to compare each continuous variable between groups. Categorical data were analyzed with the chi-squared test with 2×2 tables. We divided patients into quartiles according to their lactate to albumin ratios using the first laboratory data available upon hospital arrival. Previous studies on acute kidney injury and in-hospital cardiac arrest demonstrated that higher serum lactate to albumin ratio quartile patients had increased mortality [20,24]. Therefore, in this study, we defined the first quartile as the reference group. Characteristics and outcomes were evaluated for patients in each quartile. Multivariable logistical regression models compared serum lactate to albumin ratios and OHCA outcomes using odds ratios (ORs) and 95% confidence intervals (CIs). We analyzed biologically relevant factors, such as age and sex, that are adjusted for in clinical epidemiological studies and prehospital factors addressed by previous researchers [26,31,32] that could influence the analysis. Those variables were the following: patient age (1-year increments); patient sex (male or female); receipt of telephonic CPR guidance from the dispatcher; presence of a bystander witness to the event; performance of CPR by a bystander; first documented on-scene cardiac rhythm (shockable or nonshockable); prehospital adrenaline administration (yes or no); performance of prehospital advanced airway management (yes or no); etiology of cardiac arrest (cardiac or noncardiac and source of arrest being respiratory disease, cerebrovascular disease, or malignant tumor); and time from emergency call to the acquisition of laboratory data [26]. Data from those with first documented on-scene shockable or nonshockable cardiac rhythm were subjected to subgroup analysis. For comparisons, P<0.05 was considered significant. R ver. 4.3.2 (R Foundation for Statistical Computing) was used for statistical analysis.
RESULTS
In the JAAM-OHCA Registry, 81,234 patients with OHCA were registered between June 1, 2014, and December 31, 2021. Data for analysis were acquired from the 4,413 eligible patients who remained after exclusions for missing data or failure to meet predefined inclusion criteria (Fig. 1).
The laboratory measurements of OHCA patients according to serum lactate to albumin ratio are shown in Table 1. The median age of the patients was 73 years, and 2,914 of 4,413 patients (66.0%) were male. Patients were divided into quartiles based on serum lactate to albumin ratio: ≤2.23 (quartile 1), >2.23 and ≤3.39 (quartile 2), >3.39 and ≤4.70 (quartile 3), and >4.70 (quartile 4). The proportion of men was higher and the patients were younger in the first (lowest) lactate to albumin ratio quartile, compared with those in other quartiles. The first quartile group was more likely to have had a bystander witness, an on-scene shockable cardiac rhythm documented early in the resuscitation process, a prehospital ROSC earlier than those in the other groups, and a lower serum lactate level upon hospital arrival.
The first quartile had the largest proportion of patients surviving 30 days with favorable neurological outcomes with 558 of 1,104 patients (50.5%). The primary outcome was achieved by 240 of 1,111 patients (21.6%) in the second quartile, 96 of 1,096 patients (8.8%) in the third quartile, and 24 of 1,102 patients (2.2%) in the fourth quartile. The adjusted ORs for this outcome in the second, third, and fourth quartiles compared with the first quartile as the reference were 0.33 (95% CI, 0.26–0.42), 0.19 (95% CI, 0.14–0.26), and 0.07 (95% CI, 0.04–0.11), respectively. A similar trend was observed for 30-day survival (Table 2).
DISCUSSION
Using nationwide OHCA registry data, we identified significant associations among OHCA patients with lower serum lactate to albumin ratios and 30-day survival and favorable neurological outcomes. This tendency was the same irrespective of the first documented on-scene shockable or nonshockable cardiac rhythm. We evaluated on a national scale the dose-dependent relationship between being in the lower serum lactate to albumin ratio quartile at hospital arrival and favorable neurological outcome. In addition, these associations were consistent with findings from previous studies that included patients with other diagnoses and in other clinical settings [20–24].
Immediate OHCA patient treatment decision-making upon hospital arrival is critical even when the patient’s condition prior to the event is unknown [18]. For example, we are often unable to evaluate low-flow time, defined as the period of reduced brain blood flow during resuscitation. In this study, we could not obtain the time from the emergency call to ROSC because this information was not recorded in the registry we used. However, our findings revealed a significant association between a lower serum lactate to albumin ratio and a favorable neurological outcome among patients with OHCA categorized into quartiles based on this ratio. Therefore, we suggest that the serum lactate to albumin ratio is a useful biomarker in clinical practice. Because most patients, even those that obtain ROSC, do not achieve a favorable neurological outcome, a laboratory marker that can be quickly and easily measured would be valuable in helping physicians assess patient condition and make clinical treatment decisions [18]. This would also aid in providing patients’ families with information related to prognosis as quickly as possible, a process crucial for clinician decision-making. As early prognostic stratification of patients with OHCA should not rely on a single factor, our findings would be best used in conjunction with other multidisciplinary assessments. To enhance the utility of our findings in clinical practice, further research is needed to establish serum lactate to albumin ratio cutoff values.
Our study had some strengths. First, we had a nationwide population for this multicenter observational study [30]. Second, all cases of OHCA in hospitals participating in this registry were evaluated; and only a small proportion of records were excluded because of missing data. The proportions of patients with no available lactate level and no available albumin level were 3.9% (3,172 of 81,234) and 0.4% (296 of 81,234), respectively. Finally, both prehospital and in-hospital information, including neurological outcome, were recorded in the registry we used [30,33].
The current study also had several critical limitations. First, unmeasured factors might have influenced outcomes because this was an observational study. Data in the registry could not be used to assess several important factors that may have affected the dynamics of the serum lactate to albumin ratio. These factors included the quality of CPR provided, medical history including prescribed medications and nutritional status before the OHCA, fluid infusion during CPR, and the time from the emergency call to ROSC. Also, blood collection site (i.e., arterial or venous) during CPR were not identified. A previous study recommended confirmation of hyperlactatemia with arterial sampling in those with peripheral venous lactate levels >2 mmol/L [34]. These major unmeasured factors might have caused a critical bias in our findings. Second, those who evaluated outcomes were not blinded, but their evaluations were based on CPC scores in hospital medical records in our previous study [26]. Third, the timing of blood collection and interval from the clinical event were not equal in all enrolled patients, but we defined the timing of blood collection as the initial data collected upon hospital arrival. This reflected the variability of time intervals in clinical practice. All hospitals in Japan did not participate in the registry we used. Finally, our findings may not be globally generalizable because emergency medical systems differ widely throughout the world.
In summary, this study, which used a nationwide Japanese registry, found a significant association between being in a lower serum lactate to albumin ratio and favorable neurological outcome after OHCA.
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