心脏骤停后诱导低体温的获益受质疑

降低心脏骤停昏迷患者的核心体温可改善结局的观念也被广为接受，但在美国心脏协会(AHA)年会上发布的两项最新研究对这一观念提出了质疑。

这两项研究显示，降至低体温水平与正常体温相比、院前与院内相比，降温治疗均不能明显改善死亡率或神经结局。这两篇论文分别同期发表在《新英格兰医学杂志》和《美国医学会杂志》上。

诱导低体温目前是昏迷的院外心脏骤停存活患者的标准治疗。但一些动物模型提示，越早开始降温，结局就越好。

华盛顿大学的Francis Kim博士及其同事研究发现，在1,359例患者中，无论从何时开始进行低体温诱导，结局均基本相同(JAMA 2013 Nov. 17 [doi:10.1001/jama.2013.282173])。

研究者将患者随机分组，在现场、转运过程中或到达医院时给予诱导低体温治疗。干预组患者输注多达2 L的冰生理盐水、7~10 mg泮库溴铵和1~2 mg地西泮，目标体温为34 ℃。对照组患者在院内接受低体温诱导，根据各个医院的规定采取体表或血管内治疗。

根据有无心室颤动(VF)将患者分为两组。无VF的患者年龄更大(68岁 vs. 62岁)。其他基线特征相似，包括从拨打电话到恢复自主循环的时间、心率和血压。

结果显示，现场干预使有VF和无VF的患者的平均核心体温分别降低了大约1.2 ℃和1.3 ℃。这些患者的核心体温降至34 ℃的时间比在院内接受降温治疗的患者提前了1小时以上。

干预组和对照组在存活至出院的患者比例方面没有明显区别(有VF：63% vs. 64%；无VF：19% vs. 16%)。两组患者在出院时神经状态(完全康复或轻度受损)方面也无显著差异。在有VF的患者中，干预组和对照组分别有57%和62%的患者在出院时处于良好神经状态；在无VF的患者中，两组分别有14%和13%的患者获得了良好神经状态。

两组在从昏迷中苏醒或在昏迷中死亡的患者比例方面均无显著差异。有VF的两组患者的中位住院时间均为9天，无VF的两组患者的中位住院时间均为11天。

作者指出，有部分证据显示干预增加了伤害。干预组在转运途中再次发生心脏骤停的患者明显多于对照组(26% vs. 21%)。不仅如此，干预组患者的氧合水平明显更低，首次胸部X线显示肺水肿的几率明显更高，并且在住院头12个小时内对利尿剂的使用明显更多。

研究者指出：“重要的是，院前降低体温的方法可能与早期损害有关，掩盖了后续的改善。再次心脏骤停可能加重脑缺血，虽然不影响早期死亡率，但会增加住院后期的死亡风险。”

另一项研究提出了“诱导低体温与维持接近正常体温相比能否带来显著获益”的问题。结果显示，体温降至33 ℃的患者的结局并不优于核心体温维持在36 ℃的患者(N. Engl. J. Med. 2013 Nov. 17 [doi:10.1056/NEJMoa1310519] )。

主要研究者、瑞典赫尔辛堡医院的Niklas Nielsen医生指出：“我们的试验表明，与维持36 ℃体温相比，将体温降至33 ℃不能为院外心脏骤停的昏迷患者带来任何益处。”

这个研究团队分析了接受两种降温方案的939例患者的结局。主要终点是入组后180天全因死亡率。次要终点包括180天时死亡或不良神经结局的复合终点，采用脑功能分类(CPC)和改良Rankin量表进行评价。

干预包括36小时的降温和逐步复温。允许使用冰袋、冰水和血管内或体表温度管理措施。在28小时候开始逐步复温至37 ℃； 36小时后停止或减弱。在此之后，两组患者均接受发热控制措施，防止体温反弹至37.5 ℃以上。患者的平均年龄为64岁；多数(约75%)以VF为首要的心律失常。自主循环恢复的中位时间为心脏骤停后25分钟。所有患者在达到医院时均处于昏迷状态。中位随访256天。

对多数患者(76%)采用体表冷却系统进行体温管理；对其余患者采用血管内导管进行降温。33 ℃组有3例、36 ℃组有4例患者未接受分配的干预方案；根据临床医生的决定，33 ℃组有16例患者的复温时间早于预定方案。

在住院的第1个星期内，247例患者(33 ℃组132例、36 ℃组115例)撤除了生命支持。撤除的原因包括脑死亡、多器官衰竭和伦理问题。

在末次随访时，33 ℃组和36 ℃组分别有50%和48%的患者死亡，组间无显著差异。不论采用CPC还是改良Rankin量表进行评价，两组在死亡或不良神经结局的复合终点方面也均无明显差异。

这些结果在所有的校正后分析中、在意向治疗人群中，以及在按方案治疗人群中均相似。

不良事件较常见，33 ℃组和36 ℃组分别有93%和90%的患者发生不良事件。最常见的是低钾血症，在33 ℃组中更常见(19% vs. 13%)。

本项研究与既往支持诱导低体温治疗的研究的一个重要不同之处在于，“我们在两组中均不允许体温自然变化，而是在干预过程中积极控制体温，以防止心脏骤停后3天内出现发热。”

研究者认为，很难将上述结果与2006年的心脏骤停后降低体温研究进行比较。后者首次发现心脏骤停后降低体温有益。本项研究中两组的死亡率均低于2006年试验——很可能是由于近年来在心脏骤停患者院前和院内急救方面已取得了较大进展。

研究者指出：“与36 ℃相比，我们没有发现以33 ℃为目标体温会导致任何伤害，但也没有发现33 ℃组在任何结局指标上占有优势。”基于上述结果，需要慎重考虑院外心脏骤停患者的目标体温。

Kim博士无利益冲突披露。他的几名合著者承认与多家医疗器械公司有利益关系。Nielsen医生无利益冲突透露。他的5名合著者承认与外部实体有利益关系，但这些实体均与本研究无关。

随刊述评：包括降低体温在内的进展使我们得以成功治疗心脏骤停

Jon C. Rittenberger博士和Clifton W. Calloway博士在随刊述评中指出，Nielsen医生及其同事发现诱导低体温与维持接近正常体温相比并不能给院外心脏骤停患者带来实质性益处(N. Engl. J. Med. 2013 Nov. 17 [doi:10.1056/NEJMe1312700])。

“这项高质量研究的样本量比原有试验样本量总和(共招募352例患者)的2倍还多，并且充分运用了现代重症监护措施。”

关于这项研究为何得出不同于既往研究的结果，述评作者认为有多方面原因。其中最大的因素很可能是，数年来我们已在急诊治疗方面取得了重要进展，从而减少了单项干预措施的增量效益。

此外，不同心脏骤停患者的疾病严重程度差异较大，或许存在能从诱导低体温治疗中获益的患者亚组，但事先没有指定这类患者。尤其是如果要校正降低体温的程度和持续时间以便与脑损伤严重程度相匹配，则某个亚组的获益就可能被整体数据所掩盖。

述评作者总结道：“本项试验带给我们的最重要信息是，包括体温控制在内的现代积极治疗使得CPR后住院患者的生存率超过了死亡率。与10年前不同的是，在CPR后恢复自主循环的患者中有1/2而不是1/3可存活至出院。很少有其他医疗领域在这么短的时间内取得这么大的进步。”

Clifton W. Callaway博士是匹兹堡大学急诊医学研究所主任。他承认接受了多个心脏健康组织提供的演讲费，并持有两项心脏复苏术相关设备的专利。Jon C. Rittenberger博士是匹兹堡大学急诊医学科住院医师研究部主任。他由于进行有关急诊医学的演讲而接受了酬金和讲课费。

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By: MICHELE G. SULLIVAN, Cardiology News Digital Network

Two new studies may cast some doubt upon the now widely held belief that core cooling improves outcomes in unconscious cardiac arrest patients.

The studies, presented at the American Heart Association scientific sessions, found that neither cooling to hypothermic levels, compared with normothermic, nor prehospital, compared with in-hospital, significantly improved mortality or neurologic outcomes in more 2,000 patients. The papers were simultaneously published – one in the New England Journal of Medicine, and the other in JAMA.

Induced hypothermia is now standard of care for unconscious survivors of out-of-hospital cardiac arrests. But some animal models suggest that the earlier cooling begins, the better outcomes result.

Dr. Francis Kim and his colleagues, however, found almost identical outcomes in a group of 1,359 patients, whatever the timing of hypothermia induction (JAMA 2013 Nov. 17 [doi:10.1001/jama.2013.282173]).

Dr. Kim of the University of Washington, Seattle, and his coauthors randomized patients to induction in the field and during transport, or upon hospital arrival. The intervention group received an infusion of up to 2L of ice-cold normal saline, 7-10 mg pancuronium, and 1-2 mg diazepam, with a target temperature goal of 34°C.

In the control group, hypothermia induction occurred in the hospital, according to each site’s protocol, with either surface or intravascular regimens.

Patients were divided into two groups: those with ventricular fibrillation and those without. Patients without VF were older (68 vs. 62 years). Other baseline characteristics – including time from the call to the return of spontaneous circulation, heart rate, and blood pressure – were similar.

The in-field intervention decreased mean core temperature by about 1.2°C in patients with VF and 1.3°C in those without VF. These patients achieved the target core temperature of 34°C more than 1 hour sooner than patients cooled in the hospital.

Survival to discharge was not significantly different between the intervention and control groups (63% vs. 64% of those with VF; 19% vs. 16% of those without VF).

Nor were there significant differences in the neurologic status of full recovery or mild impairment at discharge, the investigators said. Among those with VF, good neurologic status occurred in 57% of the intervention group and 62% of the control group. For those patients without VF, good neurologic outcomes occurred in 14% of the intervention group and 13% of the control group.

There were no significant differences in the proportion of patients who awakened from coma or died without awakening in any of the groups. The median length of stay was within the VF group (9 days for both treatment groups), and among those without VF (about 11 days for each treatment group).

The intervention carried some evidence of increased harm, the authors noted. Significantly more of the intervention patients rearrested during transport (26% vs. 21% of the controls).

They also had significantly lower oxygenation, increased pulmonary edema on the first chest x-ray, and greater use of diuretics in the first 12 hours of hospitalization.

"Importantly, the method of pre-hospital hypothermia may have been associated with early harm that could have masked subsequent improvement," the investigators noted. "Rearrest possibly worsened brain ischemia that did not affect early mortality, but manifested as increased risk of death later during the hospitalization."

The second study released at the AHA meeting questioned whether induced hypothermia confers significant benefit over maintaining a near-normothermic temperature. Patients cooled to 33°C had no better outcomes than those whose core temperatures were held at 36°C, Dr. Niklas Nielsen and colleagues reported Nov. 18 (N. Engl. J. Med. 2013 Nov. 17 [doi:10.1056/NEJMoa1310519]).

"Our trial does not provide evidence that targeting a body temperature of 33° C confers any benefit for unconscious patients admitted to the hospital after out-of-hospital cardiac arrest, as compared with targeting a body temperature of 36°C," wrote Dr. Nielsen of Helsingborg Hospital, Sweden, and his colleagues.

The team analyzed outcomes for 939 patients who had been randomized to the two cooling regimens. The study’s primary outcome was all-cause mortality by 180 days after enrollment. The secondary outcomes included a composite of death or poor neurologic outcome at 180 days as evaluated with the Cerebral Performance Category (CPC) and modified Rankin scales.

The intervention consisted of 36 hours of cooling and gradual rewarming. Treatment teams were allowed to use ice packs, ice-cold fluid, and intravascular or surface temperature management. Gradual rewarming to 37°C commenced after 28 hours; this was discontinued or tapered at 36 hours. After this, patients in both groups were treated with fever-control measures to prevent a rebound temperature of above 37.5°C.

The patients were a mean of 64 years old; most of them (about 75%) had VF as the first shocked rhythm. Spontaneous circulation returned a median of 25 minutes after the arrest. All were unconscious when they arrived at the hospital. The mean follow-up was 256 days.

Most (76%) had temperature management with a surface cooling system; the rest were cooled by an intravascular catheter. Three patients in the 33°C group and four in the 36°C group didn’t get the assigned intervention; 16 in the 33°C group were rewarmed sooner than the protocol, at the discretion of their physician.

During the first week of hospitalization, 247 patients (132 in the 33°C group and 115 in the 36°C group) had life support withdrawn. Reasons for withdrawal included brain death, multiorgan failure, and ethical concerns.

At final follow-up, 50% of patients in the 33°C group and 48% in the 36°C group had died – a nonsignificant difference. There were no significant differences in the composite outcome of death or poor neurologic outcome whether measured by the CPC or the modified Rankin scales.

These results were similar in all adjusted analyses, in the intent-to-treat population, and in the per-protocol population.

Adverse events were common, occurring in 93% of the 33°C group and 90% of the 36°C group. The most common was hypokalemia, which was more significantly more common in the 33°C group (19% vs. 13%).

The study differed in one important way from others that have supported the use of induced hypothermia – and this might have had a key impact on the overall finding.

"We did not allow the natural trajectory of temperature evolution in either group," the authors said. "We actively controlled the temperature during the intervention period and aimed to prevent fever during the first 3 days after cardiac arrest."

It’s difficult to compare these results with those of the Hypothermia After Cardiac Arrest Study – the 2006 trial which first found in favor of the practice, the authors said.

Mortality in both groups of the current study was lower than that seen in 2006 – probably because of the recent advances in prehospital and in-hospital critical care management for cardiac arrest patients.

"We did not find any harm with a targeted temperature of 33°C as compared with 36°C," the investigators wrote. "However, it is worth recognizing that for all outcomes, none of the point estimates were in the direction of a benefit for the 33°C group.

On the basis of these results, decisions about which temperature to target after out-of-hospital cardiac arrest require careful consideration."

Dr. Kim had no financial disclosures. Several of his coauthors disclosed financial relationships with medical device companies. Dr. Nielsen had nothing to disclose. Five of his coauthors disclosed financial relationships with outside entities; however, none appeared to be related to the study.

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Care advances – including hypothermia – driving success in cardiac arrest

Dr. Niklas Nielsen and his colleagues found no real benefit of induced hypothermia over near-normothermic temperature maintenance in patients with out-of-hospital cardiac arrest, Dr. Jon C. Rittenberger and Dr. Clifton W. Calloway wrote in an editorial published along with the study (N. Engl. J. Med. 2013 Nov. 17 [doi:10.1056/NEJMe1312700]).

"This superbly executed study is more than twice the size of the original trials combined (which enrolled a total of 352 patients) and was conducted with meticulous attention to modern intensive care," the colleagues wrote, saying that there are multiple possible explanations for its finding.

The largest factor among these, they said, is probably the immense progress made in emergency care since the original hypothermia studies were published nearly a decade ago. "There has been evolution of intensive care over the past decade and improvements in patient care may have reduced the potential incremental benefits of a single intervention.

In addition, illness severity varies greatly among patients with cardiac arrest, and there may be subgroups of patients who do benefit from induced hypothermia but who were not designated in advance.

Particularly if the degree or duration of hypothermia must be adjusted to match the severity of brain injury, the benefits to a subgroup may be missed in a trial of one regimen of hypothermia for all comers."

The most important message of this trial, they wrote, "is that modern, aggressive care that includes attention to temperature works, making survival more likely than death when a patient is hospitalized after CPR.

"In contrast to a decade ago, one-half instead of one-third of patients with return of spontaneous circulation after CPR can expect to survive hospitalization. Few medical situations have enjoyed such absolute improvement over the same time period."

Dr. Clifton W. Callaway is the Ronald D Stewart Endowed Chair of Emergency Medicine Research at the University of Pittsburgh. He disclosed receiving speakers fees from several cardiac health groups and holding two patents on devices related to cardiac resuscitation. Dr. Jon C. Rittenberger is director of residency research in the emergency medicine department of the University of Pittsburgh. He has received honoraria and lecture fees for speaking on emergency medicine.