The effect of whole-body cooling on renal function in post-cardiac arrest patients

Cardiac Arrest (CA) and resuscitation are an example of a whole-body Ischemia/Reperfusion (I/R) injury characterized by a multi-organ dysfunction and systemic activation of the innate immune system causing a ‘sepsis-like syndrome’ [1, 2]. The restoration of spontaneous circulation (ROSC) after prolonged, complete, whole-body ischemia is an unnatural pathophysiological state created by successful cardiopulmonary resuscitation (CPR) [1]. The complex phase of resuscitation which begins when patients regain spontaneous circulation after CA has been defined by the International Liaison Committee on Resuscitation (ILCOR) as “post–cardiac arrest syndrome” [1]. The ischemia and reperfusion during CA, resuscitation and post-resuscitation phases can particularly affect the kidney: I/R injury leads to damage of epithelial cells by increased oxygen radical production [2] and peroxidation of lipids [3, 4] but also to interstitial inflammation and interstitial “micro-vasculopathy” that are involved in abnormal repair processes including incomplete repair of tubular cell and fibrosis development [4]. The cross-talk between the kidney and peripheral immune system in humans after whole-body I/R injury and the changes over time in the inflammatory response are speculative [5] and aside from cardiogenic shock limited information are available regarding predisposing factors and outcome of acute kidney injury (AKI) after CA [6, 7]. Although therapeutic hypothermia (TH), also termed targeted temperature management, is an established intervention (ILCOR/American Heart Associatio) used for neuroprotection [3, 4] though recent data challenge the benefit of TH using target temperature lower than 36 °C [8, 9]. The effect of TH on renal protection is uncertain and poorly investigated.

The purpose of this study was to investigate the effect of TH on the development of AKI and on renal outcomes in comatose patients resuscitated from CA and treated with surface cooling techniques. We hypothesized that TH could be a protective strategy against renal I/R injury while the shift from hypo- to normothermia may cause rewarming injury.

To the best of our knowledge, this is the first study suggesting that the rewarming phase after TH applied to post-CA patients may have an impact on the development of AKI. During the TH period, among all 36 patients, 21 (58%) had no evidence of AKI according to KDIGO classification. AKI is a common occurrence, in particular from out-of-hospital-CA patients. Indeed, post-cardiac arrest is characterized by a whole-body ischemia followed by reperfusion with activation of a systemic inflammatory response and release of injury products into the circulation [5, 6] responsible of additive stimuli for ischemic injury [15]. Following resuscitation from spontaneous CA, AKI is a common complication with increased mortality risk, dialysis requirement and prolonged hospital stay [7, 16, 17]. An intriguing field of research shows the capability of a decrease in whole-body temperature to limit the ischemic injuries. Although TH has been used from 1950s to protect the brain against a global ischemia after CA, there is scant data on the potential benefit of this strategy on kidney endpoints [18, 19]. Experimental studies investigated the effect of body temperature on renal susceptibility. On the basis of renal ischemic preservation by using low body temperature hypothermia, Pelkey et al. demonstrated that minimal temperature changes during renal ischemia alter functional and morphologic outcome [20]. These findings in literature showed that in animals hypothermia is able to reduce the risk of renal failure after renal I/R injury [21, 22]. Renal function is eventually depressed during hypothermia owing to a fall in systemic blood pressure and the effect of hypothermia on organ metabolism itself. As renal blood flow progressively decreases, renal vascular resistance rises, promoting a further decrease in renal flow and a subsequent decrease in glomerular filtration. Increased blood viscosity and vasoconstriction were both responsible for this reduction of flow. In the setting of TH, this effect is maintained for 24 h. In this hypothermic phase, from admission to 24 h, there is a decrease of sCr probably due to decrease in muscle metabolism. Clinical practice is based on sCr measurements to monitor renal function and classify AKI. For this reason, we used a validated criteria to define and classified AKI: KDIGO. It is presumed that TH increases urine output particularly in the induction phase, this phenomenon is called cold-induced diuresis [23]. For this reason, we decide to not consider urinary output criteria for diagnosis of AKI. Our results suggested that in the rewarming phase, which started after 24 h, there is a slight increase of sCr associated with an increase in urine output that did not correlate with diuretic dose. Rewarming is a delicate phase of therapeutic hypothermia. Similar to the brain [24], the rewarming phase seems to be very important for the kidney and we strongly believe that could be dangerous if it is not performed slowly and with adequate time duration. Our results showed that with a rewarming time more than 600 min the risk of AKI is decreased. However, it does not mean that longer rewarming times exclude any risk of AKI. Rewarming of the patient is begun 24 h after the initiation of cooling. The literature recommends rewarming slowly at a temperature of 0.3–0.5 °C every hour. It means that rewarming will take approximately 8 h [25]. Differences in the time of rewarming could impact microinflammation and AKI risk.

In our study, patients who did not develop AKI had median rewarming time of 630 min (10.5 h) whereas those who did develop AKI had a median time of 540 (9 h). Rewarming is a delicate phase of TH. Adverse consequences of rewarming on the whole body may seriously limit the protective effects of hypothermia, leading to secondary injury. In literature, previous studies showed that the rise in body temperature accompanies a vasodilation causing a rewarming shock and then careful fluid monitoring during rewarming is crucial [26]. Probably, controlled rewarming of 0.15 °C per hour should be recommended [27] Our data support this recommendation showing less AKI with rewarming time > 600 min which would translate to a rewarming rate of less than 0,4 °C/h. It should be considered that in patients with severe oliguria or anuria despite volume resuscitation, RRT should be started before rewarming to avoid hyperkalemia or metabolic acidosis due to transcellular electrolyte shifts associated with this phase [28]. Hypothermia suppresses ischemia-induced inflammatory reactions and release of pro-inflammatory cytokines [29]. In our study, we assessed inflammatory response dosing IL-6, IL-1beta and IL-18 and results supported the evidence. In addition, uIL-18, a 22 KDa pro-inflammatory cytokine, produced by immune cells, macrophages and proximal tubular cells, has a role in inflammatory processes that exacerbate renal injury during the extension phase of AKI [30, 31]. This cytokine is an early biomarker for AKI in a variety of clinical scenarios indicating the activation of inflammation in kidney [32‐34]. Our results showed that with a rewarming time less than 600 min, there is a more increase in concentration respect to those with a slower rewarming (above 600 min) supporting the hypothesis that rapid rewarming is associated with increase risk of AKI (Table 4). The study has some limitations. First, this is a single center trial with only a relative small number of patients included. Secondly, the patients were assigned to two different cooling methods in a non-randomized fashion. Thus, a bias introduced by the cooling method cannot be excluded. Our results, suggest possible harm by an insufficiently controlled and or too short rewarming period. As feasibility study, there was not a comparison with a normothermic control group. The study is too small to make conclusions about outcomes, although the results are hypothesis generating.

The hypothermia treatment, if not well performed, could be a double-edged sword for kidneys: whereas hypothermia may confer protection by reducing metabolism and oxygen consumption, rapid rewarming could nullify benefits leading to a worsening of kidney function and AKI. Additional clinical studies are needed to determine the optimal rewarming rate and strategy.