A pilot study: The Noninvasive Surface Cooling Thermoregulatory System for Mild Hypothermia Induction in Acute Myocardial Infarction (The NICAMI Study)
Article Outline
Background
Hypothermia reduces metabolic demands, limits reperfusion injury, and helps salvage the injured myocardium during ST-elevation myocardial infarction (STEMI). The aim of this study was to assess early induction of noninvasive mild hypothermia in patients with acute myocardial infarction undergoing primary percutaneous coronary intervention (PCI).
Methods
This was a safety and feasibility study of the Medivance Arctic Sun noninvasive thermoregulatory system (Medivance Inc, Louisville, Colo), used as adjunctive therapy in patients with first-time STEMI. Cooling was initiated by circulating chilled water through the Arctic Sun Energy Transfer Pads placed on the patient before primary PCI. Target temperature was 34.5°C, maintained during 3 hours. Shivering was controlled with intravenous meperidine, and meperidine-related nausea was prevented with intravenous ondansetron.
Results
Nine patients underwent successful noninvasive surface cooling. All patients were Killip class I with a mean age of 62 years (8/9 males). Successful primary stenting was performed in all patients with glycoprotein inhibitors administered in 6 of 9 cases. Mean cooling time from induction to target temperature was 79 minutes (49 minutes in the last 4 enrolled cases). Mean total cooling duration was 267 minutes. Mean peak troponin T was 5.81 μg/L. Final TIMI flow grade 3 and final TIMI perfusion grade 3 were achieved in 9 of 9 patients and in 3 of 9 patients, respectively. Mean infarct size (by Myoview single photon emission computed tomography scans) was 23%. No hemodynamic or arrhythmic instability were documented.
Conclusion
Mild hypothermia can be safely induced with noninvasive surface cooling in patients with STEMI undergoing primary PCI, allowing earlier myocardial protection before mechanical reperfusion therapy.
The goal in acute ST-elevation myocardial infarction (STEMI) is the prompt restoration of coronary blood flow with current trends favoring percutaneous coronary intervention (PCI).1, 2 Reperfusion at the epicardial and microvascular level remains the cornerstone of the initial therapy to limit ischemic injury at the cellular level. Nevertheless, reperfusion injury may still occur after adequate flow restoration and jeopardize the ischemic myocardium.
A promising avenue for myocardial salvage lies in the protective effects of clinically induced mild hypothermia. Both experimental models and clinical experience have proven the beneficial effects of this treatment modality in various clinical settings.3 Studies have previously shown reduction in myocardial infarct size resulting from diminished metabolic demands on the injured myocardium.4, 5 More recently, Dixon et al6 have shown the safety of invasively induced cooling to limit infarct size after PCI in acute myocardial infarction (AMI).
The aim of this study was to assess early induction of mild hypothermia using a novel noninvasive thermoregulatory system as adjunctive therapy in patients with STEMI undergoing primary PCI.
Methods
Study population and design
From March 2003 to September 2003, patients were enrolled in this feasibility and safety study of noninvasive surface cooling with the Arctic Sun Temperature Management System (Medivance Inc, Louisville, Colo) as adjunctive therapy in patients with an acute STEMI eligible for primary PCI. All patients presented to the Montreal Heart Institute's emergency department with chest pain compatible with ischemic pain of at least 30 minutes duration and within 6 hours of onset. The initial electrocardiographic evaluation had to show either 2-mm ST elevation in 2 consecutive anterior leads or 1-mm ST elevation in 2 consecutive inferior leads.
Exclusion criteria for the study were patients with history of previous myocardial infarction; cardiogenic shock or Killip class ≥II at the time of presentation; need for cardiopulmonary resuscitation; complete bundle branch block, ventricular paced rhythm, or atrial fibrillation on the initial ECG; any contraindication to PCI or standard medications used in conventional PCI (eg, aspirin, clopidogrel, heparin, low molecular weight heparin, direct antithrombin inhibitors, and glycoprotein receptor inhibitors); active bleeding; a history of Raynaud disease; history of clinically significant neutropenia (<1000 neutrophils/mm3) or thrombocytopenia (<100
000 platelets/mm3); major surgery or trauma within the preceding 6 weeks; nonmenopausal female patients; weight ≥114 kg (250 lb); and finally, patients who were unable or unwilling (written informed consent) to comply with the protocol.
Noninvasive thermoregulatory system
The Medivance Arctic Sun Model 2000 is a thermoregulatory feedback system that controls and monitors patient temperature within a range of 33°C to 37°C (Figure 1). This system has been used to induce mild hypothermia in healthy volunteers,7, 8 to induce mild hypothermia in cardiac arrest patients,9 and to control refractory neurogenic fever.10 The Arctic Sun Control Module incorporates a temperature control algorithm that responds to patient temperature by circulating temperature-controlled water through the Arctic Sun Energy Transfer Pads to achieve a preset target. The Energy Transfer Pads are coated with a water-based biocompatible adhesive hydrogel material, which provides close skin contact for efficient heat exchange from the water to the patient.
Figure 1.
The noninvasive cooling system.
Hypothermia protocol
The pads were placed on the patient's back, abdomen, and thighs in the emergency department with a target temperature set at 34.5°C. Before cooling, an initial dose of meperidine 0.4 mg/kg was administered intravenously (IV) for 5 minutes to provide patient comfort and to prevent shivering for the first 5 patients. In subsequent patients, the initial meperidine dose was increased to 50 mg. Ondansetron 8 mg was administered IV for 5 minutes to minimize nausea associated with meperidine injection. Additional doses of meperidine 25 to 50 mg IV bolus were administered as needed for shivering, provided the patient was alert and arousable. At all times, patients were monitored for level of consciousness, tolerance to hypothermia, and respiratory depression; the next day, they were interviewed on their recollection of their discomfort related to cooling. Oxygen saturation was monitored continuously, and arterial blood gases were drawn according to the alertness of the patient.
Induced hypothermia was to be stopped for any of the following reasons: change in vital signs from steady state lasting >10 minutes, persistent arrhythmias unrelated to the PCI procedure, or persistent shivering despite medication or temperature modulation.
After 3 hours at target, patients were rewarmed to 36.5° for 2 hours, after which, the therapy was terminated.
Percutaneous coronary intervention
Primary angioplasty and coronary stenting were performed using conventional equipment according to current standards of practice. Aspirin and IV heparin were administered to all study patients before cardiac catheterization. Use of glycoprotein receptor inhibitors was left to the operator's discretion. If the latter were used, activated clotting times of 200 to 250 seconds were selected; otherwise, a range of 250 to 350 seconds was deemed appropriate.
Evaluation of myocardial reperfusion and infarct size
Lesion morphology was classified according to the modified American College of Cardiology/American Heart Association classification.11 Angiographic evaluation of TIMI flow grade and myocardial perfusion grade were analyzed as previously published.12, 13 Myoview myocardial single photon emission computed tomography (SPECT) imaging was used to assess infarct size within 30 days from admission.
Results
Eleven patients were enrolled during the study period. All patients underwent cooling induction in the emergency department after a tentative STEMI diagnosis. However, cooling was discontinued in 2 patients: 1 had a critical left main disease and was sent for urgent CABG, whereas the other had angiographically normal coronaries and was later diagnosed with a preexcitation syndrome and asymmetric septal hypertrophy. No hypothermia-related adverse clinical event was reported. The remaining 9 patients had an angiographically documented infarct-related artery amenable to PCI (baseline characteristics shown in Table I). All study patients were Killip class I on enrollment. All primary stenting for STEMI were procedural successes, achieving TIMI grade 3 flow within an hour of cooling induction. A glycoprotein inhibitor was administered in 6 of the 9 patients.
Table I. Clinical and angiographic data
| Mild hypothermia treatment patients (n = 11) | |
|---|---|
| Baseline characteristics | |
| Age (y, SD) | 62 ± 11 |
| Sex (M/F) | 10/11 |
| Mean weight (kg) | 77 |
| Hypertension | 4 |
| Diabetes mellitus | 0 |
| Dyslipidemia | 6 |
| Smoker | 6 |
| Infarct-related artery | |
| Left anterior descending | 3 |
| Left circumflex | 1 |
| Right coronary | 5 |
| Extent of diseased vessels | |
| 1-Vessel | 6 |
| 2-Vessel | 1 |
| 3-Vessel | 3 |
| Stent deployment | 9 |
| Glycoprotein inhibitors | 6 |
| LVEF (mean, %) | 45 |
| Angiographic data⁎ | |
| Initial TIMI flow grade | |
| 0 | 7 |
| 1 | 0 |
| 2 | 1 |
| 3 | 1 |
| Lesion complexity | |
| (Modified AHA class C) | 9 |
| Final TIMI flow grade 3 | 9 |
| Final TMP grade 3 | 3 |
⁎Angiographic data of patients with severe left main disease and preexcitation syndrome were not included. |
Mild hypothermia was successfully achieved in all patients with a mean time to the target of 34.5°C of 79 minutes, with a range of 40 to 176 minutes (35°C was achieved in 61 minutes). Performance improved with each patient enrolled (Table II). The key factor in rapid consistent cooling was managing the initial dose of meperidine, which was eventually increased to 1 mg/kg bolus: a maximum of 75 mg administered before active cooling and subsequent boluses of meperidine being given to avoid shivering during the course of the treatment. Microshivering was recognized by change in cooling rate monitored by the Arctic Sun and was managed with meperidine, bringing a more efficient temperature control. This improvement helped the last 4 patients to reach the target of 34.5°C in a mean time of 46 minutes (Figure 2). No delay from arrival to the emergency department to the catheterization for primary PCI occurred. The average duration time of mild hypothermia was 267 minutes. Only 1 patient presented an episode of ventricular tachycardia at stent implantation upon restoration of TIMI 3 flow requiring electric cardioversion, which was not hampered by the cooling therapy. No other significant arrhythmia occurred throughout the immediate post-PCI period or during the remainder of the hospitalization. In addition, no electrolyte disturbance or coagulopathy were documented.
Table II. Mild therapeutic hypothermia (minutes)⁎
| Mean hypothermia times (min) | |
|---|---|
| Chest pain to emergency department | 110 |
| Emergency department to cooling induction | 39 |
| Cooling induction to target 34.5°C | 79 |
| Cooling induction to target 34.5°C in last 4 included patients | 46 |
| Cooling induction to TIMI grade 3 flow | 38 |
| Cooling, total duration | 267 |
⁎Mean meperidine dose (mg/kg per hour) = 1.04 (shivering controlled in 8/9 patients) (excluding 1 shivering noncontrolled patient). |
Figure 2.
Typical tympanic temperature curve achieved during noninvasive cooling in AMI.
Shivering was well controlled in 8 patients with a mean dose of meperidine of 1.04 mg/kg per hour over the course of the study. However, shivering was not controlled in 1 patient even with a meperidine dose of 1.26 mg/kg per hour. No respiratory depression was encountered. In 4 patients, concomitant medications including Versed, fentanyl, or morphine were required for additional sedation. A loss of verbal communication without respiratory depression occurred in these patients and was reestablished with a single dose of IV Narcan 0.2 mg. Although Narcan reversed the sedative effects of meperidine, the antishivering effects were not reversed and cooling continued without further change in the level of consciousness or incident. Verbal contact at any time has confirmed the adequate tolerance to the mild hypothermia in all patients but one (uncontrolled shivering). As stated earlier, patients who needed Narcan to recuperate the verbal contact have maintained the shivering protection and comfort from the meperidine. Postprocedure interviews revealed a positive patient perception in all cases.
All patients achieved TIMI grade 3 flow after PCI (Figure 3). Initial TIMI perfusion grade (TMPG) in all 9 patients was TMPG 0/1. After reperfusion therapy, assessment of myocardial reperfusion revealed TMPG 3 in 3 cases, no case of TMPG 2, and 6 cases that remained at TMPG 0/1. Infarct size as assessed by Myoview SPECT scans showed an average size of 23%. In addition, using SPECT imaging, mean left ventricular ejection fraction was 45%.
Figure 3.
Time course of reperfusion and cooling in the 9 patients.
Discussion
Myocardial infarction remains an important clinical entity for which thrombolytic or mechanical strategies have been proven efficacious. Recent trends have shifted focus from upstream to downstream reperfusion, and prevention of myocardial damage from ischemia reperfusion injury has become as important a goal as epicardial patency.14
Experimental models on the role of myocardial temperature and its association with tissue necrosis and infarct size extension have opened the door to new therapeutic modalities.15 Even when instituted after onset of ischemia, Hale et al5 have shown benefits from regional hypothermia in rabbit hearts; a reduction of myocardial temperature by 3.6°C resulted in a 65% reduction in infarct size.5, 16 The same group has also shown that this effect is independent of hypothermia-induced bradycardia.4 Myocardial protection afforded by mild to moderate hypothermia is achieved mainly by reduced metabolic demand, which preserves mitochondrial function and spares ATP stores during reperfusion.17
In clinical studies, induced hypothermia has resulted in favorable outcomes when used as adjunctive neuroprotective therapy after cardiac arrest without any untoward effect such as cardiac arrhythmias, coagulopathy, or sepsis.18
The COOL-MI trial was a multicenter study, which randomized 357 patients within 6 hours of their AMI onset to primary PCI with or without cooling. An invasive endovascular cooling system set up in the catheterization laboratory was used to successfully induce mild hypothermia during PCI for STEMI.6 Hypothermia was thus initiated close to first balloon inflation. Although well tolerated and safe, this means cooling did not result in a difference in infarct size between the hypothermia and control groups (17.9% vs 19.2%, P = .92) except for patients with anterior myocardial infarction who reached a core temperature ≤35°C at the time of reperfusion (n = 16) (infarct size 9.3% vs 18.2%, P = .05).19
The present single-center study assessed the safety and feasibility of noninvasively induced mild hypothermia in the setting of primary PCI in STEMI. The surface cooling by the Medivance Arctic Sun thermoregulatory system was well tolerated and did not result in any hemodynamic instability, cardiac arrhythmia, or other potential hypothermia-related adverse effects. Shivering was also well controlled by meperidine. The relatively high dose of meperidine was well tolerated and safe as previously published, requiring only limited use of Narcan20 related to concomitant use of sedatives. The main advantage to this system is the ease and rapidity of noninvasive hypothermia induction, which can be readily positioned in the emergency department immediately after patient evaluation. In tertiary centers, “no-delay” direct PCI will be the treatment of choice for AMI, and the cooling, to be beneficial, will need to be fast, faster than the time to initiate reperfusion and may be achieved with improved endovascular techniques. In the current context of patient referral to tertiary PCI-capable centers in the setting of STEMI, it would be also possible to initiate noninvasive hypothermia during transfer, thus extending myocardial protection before reperfusion. Such studies are ongoing with a new portable system.
Conclusion
In patients with STEMI undergoing primary PCI, mild hypothermia can be safely induced with noninvasive surface cooling technology, allowing the potential for earlier myocardial protection before mechanical reperfusion therapy.
Study limitations
The present study was a feasibility trial. Potential limitations of the study remain to be the small patient population and the lack of control group. Nevertheless, the clinical and angiographic data show that this noninvasive cooling system can be safely and effectively incorporated as adjunctive therapy to primary PCI in the setting of STEMI. Further randomized studies are required to confirm the applicability and efficacy of this device to a broader range of patients.
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PII: S0002-8703(05)00357-1
doi:10.1016/j.ahj.2005.02.049
© 2005 Mosby, Inc. All rights reserved.
