Renal function after out-of-hospital cardiac arrest; the influence of temperature management and coronary angiography, a post hoc study of the target temperature management trial

Cardiac arrest (CA) with a return of spontaneous circulation (ROSC) represents a multisystem insult. Although neurological injury accounts for the majority of deaths, refractory cardiovascular failure is common. The post cardiac arrest syndrome is characterised by multi-organ dysfunction as a result of an acute inflammatory response and persistent haemodynamic instability. Ischaemia-reperfusion injury and on-going shock may aggravate renal injury [1‐3]. Acute kidney injury (AKI) is common in these circumstances, affecting 12–81% of patients depending on definition and patient selection [1, 2, 4, 5]. It is possible that routine therapeutic interventions and diagnostic procedures, such as target temperature management (TTM) and scans with contrast, impact the development of organ dysfunction, including the development of AKI.

There are limited data on the renal effect of induced hypothermia and TTM after CA with ROSC. In the hypothermia after cardiac arrest study [6], patients randomised to treatment at 33 °C had a lower calculated glomerular filtration rate compared to controls [7]. In other clinical circumstances, hypothermia and rewarming had mixed effects [8, 9]. Prolonged hypothermia after coronary artery bypass surgery did not confer renoprotection, and relatively rapid rewarming to normothermia during cardiopulmonary bypass was associated with more renal dysfunction than less aggressive rewarming [10].

The acute coronary syndrome is a common cause of CA. Current recommendations for ST-elevation myocardial infarction (STEMI) after CA with ROSC include emergent coronary angiography, and if necessary, percutaneous coronary intervention (PCI) within 120 min [11]. However, in comatose CA patients after non-STEMI, the decision for angiography and the optimal timing remains controversial [11, 12]. Trials are addressing the risk-benefit ratio of emergent coronary angiography in this patient group [13, 14]. Whether early angiography impacts the risk of AKI after CA is unknown.

The aims of this post hoc analysis were to describe the incidence and outcome of AKI in survivors of out-of-hospital CA (OHCA) of presumed cardiac origin and to investigate the impact of TTM and early coronary angiography.

We performed a post hoc analysis of the target temperature management trial, a parallel group randomised clinical trial in 36 intensive care units (ICUs) in Europe and Australia between 2010 and 2013 which compared the effect of treatment at 33 °C or 36 °C following ROSC on all-cause mortality (trial registration number NCT01020916, registered on www.​ClinicalTrials.​gov 26 November 2009). The rationale and main results have already been reported [15]. Ethics committees in all participating countries approved the protocol. Waived, delayed and/or consent from legal surrogates and delayed written informed consent from patients regaining mental capacity were obtained according to decisions by ethical boards in respective countries.

Nine hundred thirty-nine patients were included in the original TTM study. Following the exclusion of 86 patients, 853 patients were included in the analyses (Additional file 1: Figure S1). The patients excluded due to early death survived 15 (IQR 10–21) hours after CA. Seven hundred six patients (82%) were males, and the median age was 65 (56–73) years. An initial shockable rhythm was present in 80% with bystander CPR performed in 625/853 patients (73%). The median time from CA to ROSC was 25 (16–38) minutes. More than 80% of the patients required vasoactive drugs during the first 3 days of intensive care and 112/859 (13%) were in shock at the time of inclusion in the study. More than half of the patients had a maximum circulatory SOFA score of 4 during the first 3 days after CA (Table 1).

During days 2–7, 138 patients (16%) had maximum AKI stage 1, 116 (14%) had AKI stage 2 and 127 (15%) had AKI stage 3 of whom 74 received RRT. There were 472 patients (55%) who did not fulfil the AKI criteria. The daily prevalence of AKI during the first week is shown in Additional file 1: Figure S2. The number of patients diagnosed with AKI based on creatinine and urinary output criteria is shown in Fig. 1. In 541 patients (264 TTM-33 and 277 TTM-36), their last day of the ICU stay was incomplete because the patient left the ICU either due to improvement or death/withdrawal of intensive care. Urine output analysis was therefore excluded for that day.

Patients who developed AKI were characterised by an older age, a greater proportion suffering from NYHA heart failure stages 3 and 4, a lower incidence of a shockable rhythm, a longer duration from CA to ROSC, a higher lactate and serum creatinine on admission and more frequent treatment with an IABP, while early angiography and TTM-36 were associated with less AKI (Table 1).

In survivors of OHCA from the presumed cardiac cause, temperature management at 33 °C did not show different rates of AKI from management at 36 °C. In addition, emergency contrast angiography within 6 h of OHCA was not associated with a higher risk of AKI compared to later or no angiography. This finding is important and should be evaluated in properly designed trials given the possibility that the number of patients managed with early angiography may increase if the recommended clinical strategy for STEMI is extended to non-STEMI.

Reported incidences of AKI after CA range from 12 to 81% depending on the definition used [1, 4]. Our finding of an incidence of AKI of 45% is in line with previous work [5, 19]. We also show an association between AKI after OHCA and increased mortality, which again is in agreement with previous reports [1, 2, 5, 19‐21].

The TTM-33 group contained more patients with AKI and more severe AKI than the TTM-36 group. The temperature groups were reasonably well balanced with regard to patient and cardiac arrest factors. We believe the exclusion of patients who died on days 1 and 2 after OHCA from our analysis did not affect our conclusions since death in the first 2 days was evenly distributed between temperature allocations. The patient characteristics were also balanced with respect to the patient and cardiac arrest factors. During the ICU stay, vasoactive drugs were used more frequently in the TTM-33 group compared to the TTM-36 group. This may reflect differences in cardiovascular performance between the groups. A previous sub-study of the TTM trial including 171 patients showed that patients randomised to TTM-33 had a reduced cardiac index and increased systemic vascular resistance compared to TTM-36 [22]. The optimal blood pressure/perfusion parameters for renal recovery after cardiac arrest are not known. In well-characterised patients with vasoplegia, an increase in MAP from 60 to 75 mmHg led to an increase in glomerular filtration rate (GFR) and Cr-EDTA clearance without further improvement with an increase to 90 mmHg [23, 24]. In OHCA patients, there is an association not only between increasing MAP and improved renal function indices, but also between increasing level of vasoactive support and decreased GFR/increased need for RRT [25]. Considering CA patients and renal function, the optimal balance between MAP and vasoactive support is not known. Patients in the TTM-33 group also received more intravenous fluids than the TTM-36 group. Fluid overload is a risk factor for development and progression of AKI [26, 27]. This aspect of clinical management after CA deserves further attention in future studies. After correction for important risk factors, temperature allocation was no longer an independent risk factor for AKI.

After correction for important risk factors, early angiography was not independently associated with an increased risk of AKI. This is encouraging, as fear of contrast-induced nephrotoxicity may lead clinical teams to withhold potentially life-saving emergency coronary angiography unnecessarily. Similar results were noted by Petek et al. [28]. Whether the TTM protocol recommendation to administer intravenous fluids on induction of TTM (30 ml/kg) modified the development of AKI is unclear.

Our principal reason for focusing on the effects of early angiography (within 6 h of CA) was to investigate a clinical scenario in which the renal system is exposed to several potentially harmful insults simultaneously. In the post CA setting, where cardiac output may be reduced, administration of contrast during emergency angiography might potentially compromise the chances of renal recovery further [29]. The lack of an increased incidence of AKI in this setting is reassuring especially in light of current guidelines [12] and consensus statements [30, 31]. Early angiography may result in faster recovery of cardiac function and better renal perfusion, which may outweigh the potential risks associated with contrast media. Our results are supported by a recent study showing no significant difference in the release of early AKI biomarkers in critically ill patients after contrast exposure [32].

Both patient characteristics and OHCA factors were associated with development of AKI. An increasing time from CA to ROSC, an indicator of ischaemic burden, was independently associated with a higher risk of AKI, as was a higher serum creatinine on admission. The association of the intensity of ischaemia/reperfusion injury after CA (whether assessed as amount of epinephrine administered, time to ROSC, lactate concentration or the early presence of shock) and AKI has been noted in several studies [3‐5, 19, 21]. Increased serum creatinine concentrations on admission and risk of AKI are also well described [4, 5, 19]. Thus, creatinine concentrations have been incorporated in most AKI risk-scoring systems [33]. The reason for the increased baseline creatinine concentration in our patient group developing AKI is not known. Patient factors (age, pre-existing cardiac failure, higher body mass index with associated muscle mass and unrecognised CKD (chronic kidney disease) and peri-arrest factors (longer time to ROSC and more pronounced post ROSC haemodynamic instability) may have contributed [34].

The presence of an IABP was strongly associated with the development of AKI, but shock and poor lactate clearance were not. Since the use of IABPs was unevenly distributed between centres, availability and indications for its application may have differed. It is possible that the use of IABP is a surrogate marker of continued haemodynamic instability and continued shock, but it is also possible that using an IABP after OHCA increases the risk of AKI per se.

Early angiography was not independently associated with a lower incidence of AKI. When extending the analysis to all patients with angiography during the ICU stay, angiography was independently associated with a reduction of AKI but the selection and survivor bias contributes to this finding.

In survivors of OHCA from the presumed cardiac cause, temperature management at 33 °C did not show different rates of AKI from management at 36 °C. Coronary angiography within 6 h of CA was not associated with an increased incidence of acute kidney injury compared to later or no coronary angiography. The additional effect of coronary angiography on kidney function after cardiac arrest was negligible compared to other factors causing acute kidney injury after cardiac arrest.

The present results suggest that coronary angiography should not be deferred in a patient after cardiac arrest due to concerns over the risk of acute kidney injury.