Dowody naukowe

Bernard, S. A., T. W. Gray, et al. (2002). „Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia.” The New England journal of medicine 346(8): 557-563.

BACKGROUND: Cardiac arrest outside the hospital is common and has a poor outcome. Studies in laboratory animals suggest that hypothermia induced shortly after the restoration of spontaneous circulation may improve neurologic outcome, but there have been no conclusive studies in humans. In a randomized, controlled trial, we compared the effects of moderate hypothermia and normothermia in patients who remained unconscious after resuscitation from out-of-hospital cardiac arrest. METHODS: The study subjects were 77 patients who were randomly assigned to treatment with hypothermia (with the core body temperature reduced to 33 degrees C within 2 hours after the return of spontaneous circulation and maintained at that temperature for 12 hours) or normothermia. The primary outcome measure was survival to hospital discharge with sufficiently good neurologic function to be discharged to home or to a rehabilitation facility. RESULTS: The demographic characteristics of the patients were similar in the hypothermia and normothermia groups. Twenty-one of the 43 patients treated with hypothermia (49 percent) survived and had a good outcome–that is, they were discharged home or to a rehabilitation facility–as compared with 9 of the 34 treated with normothermia (26 percent, P=0.046). After adjustment for base-line differences in age and time from collapse to the return of spontaneous circulation, the odds ratio for a good outcome with hypothermia as compared with normothermia was 5.25 (95 percent confidence interval, 1.47 to 18.76; P=0.011). Hypothermia was associated with a lower cardiac index, higher systemic vascular resistance, and hyperglycemia. There was no difference in the frequency of adverse events. CONCLUSIONS: Our preliminary observations suggest that treatment with moderate hypothermia appears to improve outcomes in patients with coma after resuscitation from out-of-hospital cardiac arrest.

HACA study group (2002). „Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest.” The New England journal of medicine 346(8): 549-556.

BACKGROUND: Cardiac arrest with widespread cerebral ischemia frequently leads to severe neurologic impairment. We studied whether mild systemic hypothermia increases the rate of neurologic recovery after resuscitation from cardiac arrest due to ventricular fibrillation. METHODS: In this multicenter trial with blinded assessment of the outcome, patients who had been resuscitated after cardiac arrest due to ventricular fibrillation were randomly assigned to undergo therapeutic hypothermia (target temperature, 32 degrees C to 34 degrees C, measured in the bladder) over a period of 24 hours or to receive standard treatment with normothermia. The primary end point was a favorable neurologic outcome within six months after cardiac arrest; secondary end points were mortality within six months and the rate of complications within seven days. RESULTS: Seventy-five of the 136 patients in the hypothermia group for whom data were available (55 percent) had a favorable neurologic outcome (cerebral-performance category, 1 [good recovery] or 2 [moderate disability]), as compared with 54 of 137 (39 percent) in the normothermia group (risk ratio, 1.40; 95 percent confidence interval, 1.08 to 1.81). Mortality at six months was 41 percent in the hypothermia group (56 of 137 patients died), as compared with 55 percent in the normothermia group (76 of 138 patients; risk ratio, 0.74; 95 percent confidence interval, 0.58 to 0.95). The complication rate did not differ significantly between the two groups. CONCLUSIONS: In patients who have been successfully resuscitated after cardiac arrest due to ventricular fibrillation, therapeutic mild hypothermia increased the rate of a favorable neurologic outcome and reduced mortality.

Arrich, J., M. Holzer, et al. (2010). „Cochrane corner: hypothermia for neuroprotection in adults after cardiopulmonary resuscitation.” Anesthesia and analgesia 110(4): 1239.

BACKGROUND: Good neurologic outcome after cardiac arrest is hard to achieve. Interventions during the resuscitation phase and treatment within the first hours after the event are critical. Experimental evidence suggests that therapeutic hypothermia is beneficial, and a number of clinical studies on this subject have been published. OBJECTIVES: We performed a systematic review and meta-analysis to assess the effectiveness of therapeutic hypothermia in patients after cardiac arrest. Neurologic outcome, survival and adverse events were our main outcome parameters. We aimed to perform individual patient data analysis if data were available, and to from subgroups according to the cardiac arrest situation. SEARCH STRATEGY: We searched the following databases: the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, 2007 Issue 1); MEDLINE (1971 to January 2007); EMBASE (1987 to January 2007); CINAHL (1988 to January 2007); PASCAL (2000 to January 2007); and BIOSIS (1989 to January 2007). SELECTION CRITERIA: We included all randomized controlled trials assessing the effectiveness of the therapeutic hypothermia in patients after cardiac arrest without language restrictions. Studies were restricted to adult populations cooled with any cooling method applied within six hours of cardiac arrest. DATA COLLECTION AND ANALYSIS: Validity measures, the intervention, outcome parameters and additional baseline variables were entered into the database. Meta-analysis was only done for a subset of comparable studies with negligible heterogeneity. For these studies individual patient data were available. MAIN RESULTS: Four trials and one abstract reporting on 481 patients were included in the systematic review. Quality of the included studies was good in three out of five included studies. For the three comparable studies on conventional cooling methods all authors provided individual patient data. With conventional cooling methods patients in the hypothermia group were more likely to reach a best cerebral performance categories score of one or two (CPC, five point scale; 1=good cerebral performance, to 5=brain death) during hospital stay (individual patient data; RR, 1.55; 95% CI 1.22 to 1.96) and were more likely to survive to hospital discharge (individual patient data; RR, 1.35; 95% CI 1.10 to 1.65) compared to standard post-resuscitation care. Across all studies there was no significant difference in reported adverse events between hypothermia and control. AUTHORS’ CONCLUSIONS: Conventional cooling methods to induce mild therapeutic hypothermia seem to improve survival and neurologic outcome after cardiac arrest. Our review supports the current best medical practice as recommended by the International Resuscitation Guidelines.

Knapik P, Rychlik W et al. „Comparison of intravascular and conventional hypothermia after cardiac arrest.” Kardiol Pol. 2011;69(11):1157-63.

BACKGROUND: Therapeutic hypothermia is currently the best-documented method of improving neurological outcomes in patients after cardiac arrest and successful resuscitation. There is a variety of methods for lowering body temperature.
However, there are no data showing that any specific method of cooling improves
the results or increases survival. A simple method involving surface cooling and
ice-cold intravenous fluids, as well as more technologically advanced methods,
are used in clinical practice. One of the more advanced methods is intravascular
hypothermia, during which cooling is carried out with the use of a special
catheter located in the central vein.
AIM: To compare cooling with the use of intravascular hypothermia and cooling
using the traditional method.
METHODS: A prospective study was performed in 41 patients with acute coronary
syndromes who did not regain consciousness after out-of-hospital or in-hospital
cardiac arrest and restoration of spontaneous circulation. Therapeutic
hypothermia (32-34°C) was obtained with the use of an intravascular method (group
A, n = 20) or a traditional method (group B, n = 21) for a period of 24 hours.
Intravascular cooling involved the use of a catheter inserted in the femoral vein
connected to a heat exchanger (Alsius Coolgard, Zoll, Chelmsford, MA, USA).
Traditional cooling was carried out using uncontrolled surface cooling, ice-cold
intravenous fluids and ice-cold gastric lavage. Nasopharyngeal and urinary
bladder temperatures were recorded hourly. The main analysed temperature was the
urinary bladder temperature, as the heat exchanger in the intravascular
hypothermia group was controlled by the readings taken from this site.
Temperature profiles were compared.
RESULTS: Temperature < 34°C was reached in 19 (95.0%) patients in group A and in
11 (52.4%) patients in group B (p = 0.004). Stable temperature profile
(temperature in the range 32-34°C during the final 12 h of cooling) was reached
in 16 (80%) patients in group A and in three (14.3%) patients in group B (p <
0.001). Periods of inadequate cooling (temperature > 34°C) and temperature
overshoots (temperature < 32°C) were significantly more frequent in group B.
Temperature profiles were significantly different in both groups in the readings
taken from both sites. Conclusions: The presented technique of intravascular
hypothermia provides more precise temperature control in comparison with the
traditional method.

Storm C, Steffen I, Schefold JC, Krueger A, Oppert M, Jorres A, et al. Mild therapeutic hypothermia shortens intensive care unit stay of survivors after out-of-hospital cardiac arrest compared to historical controls. Crit Care. 2008;12(3):R78.

INTRODUCTION: Persistent coma is a common finding after cardiac arrest and has profound ethical and economic implications. Evidence suggests that therapeutic hypothermia improves neurological outcome in these patients. In this analysis, we investigate whether therapeutic hypothermia influences the length of intensive care unit (ICU) stay and ventilator time in patients surviving out-of-hospital cardiac arrest. METHODS: A prospective observational study with historical controls was conducted at our medical ICU. Fifty-two consecutive patients (median age 62.6 years, 43 males, 34 ventricular fibrillation) submitted to therapeutic hypothermia after out-of-hospital cardiac arrest were included. They were compared with a historical cohort (n = 74, median age 63.8 years, 53 males, 43 ventricular fibrillation) treated in the era prior to hypothermia treatment. All patients received the same standard of care. Neurological outcome was assessed using the Pittsburgh cerebral performance category (CPC) score. Univariate analyses and multiple regression models were used. RESULTS: In survivors, therapeutic hypothermia and baseline disease severity (Acute Physiology and Chronic Health Evaluation II [APACHE II] score) were both found to significantly influence ICU stay and ventilator time (all P < 0.01). ICU stay was shorter in survivors receiving therapeutic hypothermia (median 14 days [interquartile range (IQR) 8 to 26] versus 21 days [IQR 15 to 30] in the control group; P = 0.017). ICU length of stay and time on ventilator were prolonged in patients with CPC 3 or 4 compared with patients with CPC 1 or 2 (P = 0.003 and P = 0.034, respectively). Kaplan-Meier analysis showed improved probability for 1-year survival in the hypothermia group compared with the controls (log-rank test P = 0.013).

CONCLUSIONS: Therapeutic hypothermia was found to significantly shorten ICU stay and time of mechanical ventilation in survivors after out-of-hospital cardiac arrest. Moreover, profound improvements in both neurological outcome and 1-year survival were observed.

Tømte Ø, Drægni T et al. „A comparison of intravascular and surface cooling techniques in comatose cardiac arrest survivors.” Crit Care Med. 2011 Mar;39(3):443-9.

OBJECTIVES: Mild therapeutic hypothermia after out-of-hospital cardiac arrest is
usually achieved either by surface cooling or by core cooling via the patient’s
bloodstream. We compared modern core (Coolgard) and surface (Arctic Sun) cooling
devices with a zero hypothesis of equal cooling, complications, and neurologic
outcomes. DESIGN: Single-center observational study. SETTING: University hospital medical and cardiac intensive care units. PATIENTS: One hundred sixty-seven consecutive patients comatose after out-of-hospital cardiac arrest of all causes treated with mild therapeutic hypothermia in a 5-yr period. INTERVENTIONS: Nonrandomized allocation to core or surface cooling depending on availability and physician preference.
MEASUREMENTS AND MAIN RESULTS: All out-of-hospital cardiac arrest patients’
records were reviewed for relevant data regarding medical history, cardiac arrest
event, prehospital care, in-hospital treatment, and complications. Survivor
neurologic function was reassessed at follow-up after 6 to 12 months. Baseline
patient and arrest episode characteristics were similar in the treatment groups.
There was no significant difference in survival with good neurologic function,
either to hospital discharge (surface, 34/90, 38%; core, 34/75, 45%; p=.345) or
at follow-up (surface, 34/88, 39%; core, 34/75, 45%; p=.387). Time from cardiac
arrest to achieving mild therapeutic hypothermia was equal with both devices
(surface, 273 min, interquartile range 158-330; core, 270 min, interquartile
range 190-360; p=.479). There were significantly more episodes of sustained
hyperglycemia among the surface-cooled patients (surface, 64/92, 70%; core,
36/75, 48%; p=.005) and significantly more hypomagnesaemia among core-cooled
patients (surface, 16/87, 18%; core, 27/74, 37%; p=.01).
CONCLUSIONS: In this study, surface and core cooling of out-of-hospital cardiac
arrest patients following the same established postresuscitation treatment
protocol resulted in similar survival to hospital discharge and comparable
neurologic function at follow-up.

Cullen, D., D. Augenstine, et al. (2011). „Therapeutic hypothermia initiated in the pre-hospital setting: a meta-analysis.” Advanced emergency nursing journal 33(4): 314-321.

After resuscitation of the cardiac arrest patient, reperfusion to the brain begins a cascade of events that may lead to permanent brain damage. Cooling suppresses the inflammatory response related to ischemia and metabolic demand, improving oxygen supply to anoxic areas. Until recently, cooling was only performed in the hospital setting. Recent studies have questioned whether initiating the cooling process immediately after resuscitation is beneficial in the pre-hospital setting. The primary purpose of this study was to examine the feasibility and safety of pre-hospital hypothermia via data extraction from randomized controlled trials and statistical meta-analysis. Studies included in this analysis did show a significant statistical difference with the ability to lower the body temperature when beginning pre-hospital cooling immediately, making it feasible to start therapeutic hypothermia in the pre-hospital setting. Further research is needed to determine neurological and discharge outcomes as the studies were not powered to determine statistical significance.

Hachimi-Idrissi, S., L. Corne, et al. (2001). „Mild hypothermia induced by a helmet device: a clinical feasibility study.” Resuscitation 51(3): 275-281.

STUDY OBJECTIVE: To test the feasibility and the speed of a helmet device to achieve the target temperature of 34 degrees C in unconscious after out of hospital cardiac arrest (CA). METHODS: Patients with cardiac arrest due to asystole or pulseless electrical activity (PEA) who remained unconscious after restoration of spontaneous circulation (ROSC) were enrolled in the study and randomised into two groups: a normothermic group (NG) and a hypothermic group (HG). Bladder and tympanic temperature were monitored every 15 min. A helmet device was used to induce mild hypothermia in the HG. Later on, the effect of mild hypothermia on the haemodynamics, electrolytes, lactate, arterial pH, CaO2, CvO2 and O2 extraction ratio were analysed and compared to the values obtained from the NG. RESULTS: Thirty patients were eligible for the study, 16 were randomised into the HG and 14 were randomised into the NG. The median tympanic temperature at admission in both groups was 35.5 degrees C (range: 33.3-38.5 degrees C) and the median tympanic temperature after haemodynamic stabilisation was 35.7 degrees C (range: 33.6-38.2 degrees C). In the HG, the core and the central target temperature of 34 degrees C were achieved after a median time of 180 and 60 min, respectively after ROSC. At the start of the study, no significant differences between the NG and HG were seen. At the end of the study, lactate concentration and O2 extraction ratio were significantly lower in the HG; however the CvO2 was significantly lower in the NG. CONCLUSIONS: Mild hypothermia induced by a helmet device was feasible, easy to perform, inexpensive and effective, with no increase in complications.

Holzer, M., S. A. Bernard, et al. (2005). „Hypothermia for neuroprotection after cardiac arrest: systematic review and individual patient data meta-analysis.” Critical care medicine 33(2): 414-418.

OBJECTIVE: Only a few patients survive cardiac arrest with favorable neurologic recovery. Our objective was to assess whether induced hypothermia improves neurologic recovery in survivors of primary cardiac arrest. DATA SOURCE: Studies were identified by a computerized search of MEDLINE, EMBASE, CINAHL, PASCAL, the Cochrane Controlled Trial Register, and BIOSIS. STUDY SELECTION: We included randomized and quasi-randomized, controlled trials of adults who were successfully resuscitated, where therapeutic hypothermia was applied within 6 hrs after arrival at the emergency department and where the neurologic outcome was compared. We excluded studies without a control group and studies with historical controls. DATA EXTRACTION: All authors of the identified trials supplied individual patient data with a predefined set of variables. DATA SYNTHESIS: We identified three randomized trials. The analyses were conducted according to the intention-to-treat principle. Summary odds ratios were calculated using a random effects model and translated into risk ratios. More patients in the hypothermia group were discharged with favorable neurologic recovery (risk ratio, 1.68; 95% confidence interval, 1.29-2.07). The 95% confidence interval of the number-needed-to-treat to allow one additional patient to leave the hospital with favorable neurologic recovery was 4-13. One study followed patients to 6 months or death. Being alive at 6 months with favorable functional neurologic recovery was more likely in the hypothermia group (risk ratio, 1.44; 95% confidence interval, 1.11-1.76). CONCLUSIONS: Mild therapeutic hypothermia improves short-term neurologic recovery and survival in patients resuscitated from cardiac arrest of presumed cardiac origin. Its long-term effectiveness and feasibility at an organizational level need further research.

Kim, Y. M., H. W. Yim, et al. (2012). „Does therapeutic hypothermia benefit adult cardiac arrest patients presenting with non-shockable initial rhythms?: A systematic review and meta-analysis of randomized and non-randomized studies.” Resuscitation 83(2): 188-196.

BACKGROUND: The benefit of therapeutic hypothermia (TH) for comatose adult patients with return of spontaneous circulation after cardiac arrest (CA) with non-shockable initial rhythms is uncertain. We evaluated whether TH reduces mortality and improves neurological outcome in comatose adults resuscitated from non-shockable CA. METHODS: We searched PubMed, EMBASE, CENTRAL, and BIOSIS through March 2010, to identify studies using TH after non-shockable CA. Randomized and non-randomized studies (RS and NRS) comparing survival or neurological outcome in TH and standard care or normothermia were selected. We corresponded with authors to clarify data missing from published articles. Individual and pooled statistics were calculated as risk ratios (RRs) with 95% confidence interval (CI). Both fixed- and random-effects models were used for both meta-analyses. FINDINGS: Two RS and twelve NRS were included in the meta-analysis and separately analyzed. The pooled RR for 6-month mortality of two RS was 0.85 (95% CI 0.65-1.11). The pooled RR for in-hospital mortality for 10 NRS was 0.84 (95% CI 0.78-0.92) and for poor neurological outcome on discharge was 0.95 (95% CI 0.90-1.01) in random-effects model. In subgroup analysis for the NRS with out-of-hospital CA, the pooled RR for in-hospital mortality was 0.86 (95% CI 0.76-0.99) and for the poor neurological outcome on discharge was 0.96 (95% CI 0.90-1.02). For the prospective NRS, the pooled RR for in-hospital mortality was 0.76 (95% CI 0.65-0.89) and for the poor neurological outcome on discharge was 0.96 (95% CI 0.90-1.02). Most of studies had substantial risks of bias and overall quality of evidence was very low. INTERPRETATION: TH is associated with reduced in-hospital mortality for adults patients resuscitated from non-shockable CA. However, most of the studies had substantial risks of bias and quality of evidence was very low. Further high quality randomized clinical trials would confirm the actual benefit of TH in this population.

Mongardon N, Perbet S et al. „Infectious complications in out-of-hospital cardiac arrest patients in the therapeutic hypothermia era.” Crit Care Med. 2011 Jun;39(6):1570-1.

OBJECTIVES: Infectious complications are frequently reported in critically ill
patients, especially after cardiac arrest. Recent and widespread use of
therapeutic hypothermia has raised concerns about increased septic complications,
but no specific reappraisal has been performed. We investigated the infectious
complications in cardiac arrest survivors and assessed their impact on morbidity
and long-term outcome. DESIGN: Retrospective review of a prospectively acquired intensive care unit database. SETTING: A 24-bed medical intensive care unit in a French university hospital. PATIENTS: Between March 2004 and March 2008, consecutive patients admitted for management of resuscitated out-of-hospital cardiac arrest were considered.
Patients dying within 24 hrs were excluded. All patients’ files were reviewed to
assess the development of infection. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of the 537 patients admitted after cardiac arrest,
421 were included and 281 patients (67%) presented 373 infectious complications.
Pneumonia was the most frequent (318 episodes), followed by bloodstream
infections (35 episodes) and catheter-related infections (11 episodes). When
grouped together, Gram-negative bacteria were the most frequently isolated
infectious germs (64%), but the main pathogen detected was Staphylococcus aureus
(57 occurrences). Both application itself (83 vs. 73%; p = .02) and duration
(1244 vs. 1176 mins; p = .05) of therapeutic hypothermia were significantly more
frequent in infected patients. Infection was associated with increased mechanical
ventilation duration (6 [2-9] vs. 3 [2-5.5] days; p < .001) and intensive care
unit length of stay (7 [4-10] vs. 3 [2-7] days; p < .001). Nonetheless, there was
no impact on intensive care unit mortality (174 [62%] vs. 92 [66%] patients; p =
.45) or on favorable neurologic outcome (cerebral performance category 1-2, 102
[36%] vs. 47 [34%] patients; p = .58). CONCLUSIONS: Infectious complications are frequent after cardiac arrest and may be even more frequent after therapeutic hypothermia. Despite increase in care costs, long-term and clinically relevant outcomes do not seem to be impaired. This should not discourage the use of therapeutic hypothermia in cardiac arrest survivors.

Merchant RM, Abella BS et al. „Therapeutic hypothermia after cardiac arrest: unintentional overcooling is common using ice packs and conventional cooling blankets.”  Crit Care Med. 2006 Dec;34(12 Suppl):S490-4.

OBJECTIVES: Although therapeutic hypothermia for cardiac arrest survivors has
been shown to improve neurologically intact survival, optimal methods to ensure
controlled induction and maintenance of cooling are not clearly established.
Precise temperature control is important to evaluate because unintentional
overcooling below the consensus target range of 32-34 degrees C may place the
patient at risk for serious complications. We sought to measure the prevalence of
overcooling (<32 degrees C) in postarrest survivors receiving primarily
noninvasive cooling.
DESIGN: Retrospective chart review of postarrest patients.
SETTING: Three large teaching hospitals.
PATIENTS: Cardiac arrest survivors receiving therapeutic hypothermia.
INTERVENTIONS: Charts were reviewed if primarily surface cooling was used with a
target temperature goal between 32 degrees C and 34 degrees C.
MEASUREMENTS AND MAIN RESULTS: Of the 32 cases reviewed, overcooling lasting for
>1 hr was identified as follows: 20 of 32 patients (63%) reached temperatures of
<32 degrees C, 9 of 32 (28%) reached temperatures of <31 degrees C, and 4 of 32
(13%) reached temperatures of <30 degrees C. Of those with overcooling of <32
degrees C, 6 of 20 (30%) survived to hospital discharge, whereas of those without
overcooling, 7 of 12 (58%) survived to hospital discharge (p = not significant).
CONCLUSIONS: The majority of the cases reviewed demonstrated unintentional
overcooling below target temperature. Improved mechanisms for temperature control
are required to prevent potentially deleterious complications of more profound



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