Søren Boesgaard

Targeted Temperature Management at 33°C versus 36°C after Cardiac Arrest

BACKGROUND Unconscious survivors of out-of-hospital cardiac arrest have a high risk of death or poor neurologic function. Therapeutic hypothermia is recommended by international guidelines, but the supporting evidence is limited, and the target temperature associated with the best outcome is unknown. Our objective was to compare two target temperatures, both intended to prevent fever. METHODS In an international trial, we randomly assigned 950 unconscious adults after out-of-hospital cardiac arrest of presumed cardiac cause to targeted temperature management at either 33°C or 36°C. The primary outcome was all-cause mortality through the end of the trial. Secondary outcomes included a composite of poor neurologic function or death at 180 days, as evaluated with the Cerebral Performance Category (CPC) scale and the modified Rankin scale. RESULTS In total, 939 patients were included in the primary analysis. At the end of the trial, 50% of the patients in the 33°C group (235 of 473 patients) had died, as compared with 48% of the patients in the 36°C group (225 of 466 patients) (hazard ratio with a temperature of 33°C, 1.06; 95% confidence interval [CI], 0.89 to 1.28; P=0.51). At the 180-day follow-up, 54% of the patients in the 33°C group had died or had poor neurologic function according to the CPC, as compared with 52% of patients in the 36°C group (risk ratio, 1.02; 95% CI, 0.88 to 1.16; P=0.78). In the analysis using the modified Rankin scale, the comparable rate was 52% in both groups (risk ratio, 1.01; 95% CI, 0.89 to 1.14; P=0.87). The results of analyses adjusted for known prognostic factors were similar. CONCLUSIONS In unconscious survivors of out-of-hospital cardiac arrest of presumed cardiac cause, hypothermia at a targeted temperature of 33°C did not confer a benefit as compared with a targeted temperature of 36°C. (Funded by the Swedish Heart-Lung Foundation and others; TTM ClinicalTrials.gov number, NCT01020916.).

Autoregulation of Cerebral Blood Flow in Patients Resuscitated From Cardiac Arrest

Background and Purpose— Under normal circumstances, autoregulation maintains cerebral blood flow (CBF) constant within a wide range of mean arterial pressure (MAP). It remains unknown whether patients resuscitated from cardiac arrest have preserved CBF autoregulation. In this study, CBF autoregulation was investigated within the first 24 hours after resuscitation from cardiac arrest. Methods— Eighteen patients and 6 healthy volunteers had relative changes in CBF determined by transcranial Doppler mean flow velocity (Vmean) in the middle cerebral artery during a stepwise rise in MAP by use of norepinephrine infusion. Vmean was plotted against MAP, and a lower limit of autoregulation was identified by double regression analysis based on the least-squares method. Results— In patients, Vmean increased from a median of 33 (range 19 to 73) to 37 (22 to 100) cm/s (P <0.001) during a norepinephrine-induced rise in MAP from 78 (46 to 118) to 106 (60 to 149) mm Hg. Eight of 18 patients had impaired CBF autoregulation, and in 5 of the 10 patients with preserved CBF autoregulation, the lower limit of autoregulation could be identified. The lower limit of CBF autoregulation was 76 mm Hg (41 to 105 mm Hg) in the volunteers and 114 mm Hg (80 to 120 mm Hg) in the 5 patients with preserved autoregulation (P <0.01). Conclusions— We conclude that in a majority of patients in the acute phase after cardiac arrest, cerebral autoregulation is either absent or right-shifted. These results indicate that MAP should be kept at a higher level than commonly accepted to secure cerebral perfusion. We recommend, however, that further randomized clinical trials are performed to determine whether sympathomimetic drugs improve neurological outcome.

Incidence of ventricular arrhythmias in patients on long-term support with a continuous-flow assist device (HeartMate II).

The incidence of ventricular tachycardia (VT) or ventricular fibrillation (VF) in patients supported with a continuous-flow left ventricular assist device (LVAD) has not been investigated in detail. In 23 consecutive recipients of a HeartMate II, we analyzed the incidence of VT/VF during a total of 266 months of follow-up. Sustained VT or VF occurred in 52% of the patients, with the majority of arrhythmias occurring in the first 4 weeks after LVAD implantation. VT/VF requiring implantable cardioverter-defibrillator (ICD) shock or external defibrillation occurred in 8 patients and significant hemodynamic instability ensued in 3 patients. There were no clear predictors of VT/VF, and it is argued that prophylactic ICD implantation should be considered in patients supported with a continuous-flow LVAD.

N-terminal proBNP and mortality in hospitalised patients with heart failure and preserved vs. reduced systolic function: data from the prospective Copenhagen Hospital Heart Failure Study (CHHF).

Preserved systolic function among heart failure patients is a common finding, a fact that has only recently been fully appreciated. The aim of the present study was to examine the value of NT‐proBNP to predict mortality in relation to established risk factors among consecutively hospitalised heart failure patients and secondly to characterise patients in relation to preserved and reduced systolic function.

Cardiogenic shock complicating acute myocardial infarction; prognostic impact of early and late shock development.

AIMS Cardiogenic shock accounts for the majority of deaths following acute myocardial infarction. The majority of outcome data on this issue are, however, derived from single hospitals, referral centers or selected patients in randomized studies. The purpose of this study was to investigate incidence, outcome and prognostic significance of cardiogenic shock in 6676 consecutive patients with acute myocardial infarction. METHODS AND RESULTS Demographic and clinical data including the presence of cardiogenic shock were prospectively collected in 6676 non-invasively managed patients with myocardial infarction consecutively admitted to 27 different hospitals during a 2-year period. Six-year mortality data were collected in 99.9% of the population. Cardiogenic shock developed in 444 patients (6.7%). In 59% of these patients cardiogenic shock developed within 48 h, 11% developed shock during days 3 and 4 and 30% later than 4 days after the infarction. Thirty-day and 6-year mortality was 62 and 88% among shock patients compared to 9 and 45% in non-shock patients. Patients with early shock development (days 1-2) had a significantly lower 30-day mortality (45%) than those with intermediate or late shock development (>80%) (P<0.05). In 30-day survivors, survival the following years was lower than in patients without cardiogenic shock but with post-infarction heart failure. CONCLUSIONS In this nationwide prospectively collected registry, non-invasively managed consecutive myocardial infarct patients with cardiogenic shock had an extremely reduced life expectancy. Every attempt to improve treatment, prevention and identification of patients at risk of shock development should be strongly encouraged.

In Vivo Nitrate Tolerance Is Not Associated With Reduced Bioconversion of Nitroglycerin to Nitric Oxide

BACKGROUND In vitro data suggest that reduced bioconversion of nitroglycerin (NTG) to nitric oxide (NO) contributes to the development of vascular and hemodynamic tolerance to NTG. We examined the in vivo validity of this hypothesis by measuring NTG-derived NO formation by in vivo spin-trapping of NO in vascular tissues from nitrate-tolerant and -nontolerant rats. METHODS AND RESULTS Five groups (n = 6 to 8 each) of conscious chronically catheterized rats received NTG (0.2 or 1 mg/h IV) for 72 hours (nitrate-tolerant groups). Four other groups received either NTG vehicle (placebo, for 72 hours) or were left untreated (control). Nitrate tolerance was substantiated by a reduced (55% to 85%) hypotensive response to NTG in vivo and a reduced relaxation to NTG in isolated aortic rings. NTG-derived NO formation in aorta, vena cava, heart, and liver was measured as NOFe(DETC)2 and NO-heme complexes formed in vivo during 35 minutes combined with ex vivo cryogenic electron spin resonance spectroscopy. NO formation was significantly (P < .05) increased in all tissues in nitrate-tolerant rats in an NTG dose-dependent manner. Furthermore, the amount of NO formed from a bolus dose of NTG (6.5 mg/kg over 20 minutes) was similar in nitrate-tolerant and -nontolerant rats. CONCLUSIONS The results suggest that vascular and hemodynamic NTG tolerance occurs despite high and similar rates of NO formation by NTG in tolerant and nontolerant target tissues. This finding is compatible with the assumption that reduced biological activity of NO, rather than reduced bioconversion of NTG to NO, contributes to in vivo development of nitrate tolerance.

Tertiary centres have improved survival compared to other hospitals in the Copenhagen area after out-of-hospital cardiac arrest ☆

AIMS Out-of-hospital cardiac arrest (OHCA) has been reported to carry very varying morbidity and mortality. However, it remains unclear whether this is caused by intrinsic factors of the OHCA or due to the level of in-hospital care. The aim of this study is to compare 30-day and long-term mortality after OHCA at tertiary heart centres and non-tertiary university hospitals. METHODS AND RESULTS Data from the Copenhagen OHCA registry from June 2002 through December 2010 included a total of 1218 consecutive patients treated by the same mobile emergency care unit (MECU) with either return of spontaneous circulation (ROSC) or on-going resuscitation (n=53) at hospital arrival. The MECU transported patients to the nearest hospital unless an ECG on scene suggested ST-segment elevation myocardial infarction, in which case patients were transported to the nearest tertiary centre for acute coronary angiography. Therefore, patients with ST-elevation myocardial infarction (n=198) were excluded from the analysis. 30-day mortality was 56% vs. 76% and long term (up to 8years) mortality was 78% vs. 94% for tertiary and non-tertiary hospitals, respectively, both p<0.001. Multivariate analysis showed that admission to a non-tertiary hospital was independently associated with increased risk of death (HR=1.32, 95% CI: 1.09-1.59, p=0.004). Exclusion of patients with on-going resuscitation at admission resulted in HR=1.34 (1.11-1.62), p=0.003. A matched pair propensity score analysis of 255 patients confirmed the results of the proportional hazard analysis (HR=1.35, 95% CI: 1.11-1.65 p=0.003). CONCLUSION Admission to tertiary centres is associated with lower mortality rates after OHCA compared with non-tertiary hospitals.

Tetrahydrobiopterin improves endothelium-dependent vasodilation in nitroglycerin-tolerant rats.

Tolerance to nitroglycerin is caused by a nitroglycerin-mediated increase in vascular superoxide anion production. Administration of tetrahydrobiopterin (co-factor for endogenous nitric oxide (NO) formation) may potentially influence nitroglycerin tolerance in at least two different ways. Firstly, tetrahydrobiopterin may act as a scavenger of the nitroglycerin-mediated production of superoxide anions. Secondly, tetrahydrobiopterin may protect endothelial NO synthesis from the deleterious effects of increased oxidative stress. This study investigates whether in vivo nitroglycerin tolerance is affected by tetrahydrobiopterin supplementation and assesses the in vivo role of tetrahydrobiopterin in endogenous NO-mediated vasodilation in normal and nitroglycerin-tolerant rats. The results show that tetrahydrobiopterin does not affect nitroglycerin-derived, NO-mediated vasodilation, but reduces baseline mean arterial blood pressure (by 8 mm Hg, P<0.05) and normalizes endothelium-dependent responses to N(G)-monomethyl-L-arginine (L-NMMA) (from 7+/-1 to 22+/-4 mm Hg, P<0.05) in nitroglycerin-tolerant rats. It is concluded that altered bioavailability of tetrahydrobiopterin is involved in the pathophysiology of endothelial dysfunction seen in nitroglycerin tolerance.

Nitrate tolerance impairs nitric oxide-mediated vasodilation in vivo

OBJECTIVES Nitroglycerin (NTG) is metabolized to nitric oxide (NO) in vascular smooth muscle cells. It is currently not clear whether prolonged exposure to NTG and tolerance development directly affects endogenous NO-mediated vasodilation in vivo. This study investigates NO-mediated vasodilation in conscious chronically catheterized rats before and after development of nitrate tolerance. The effect of the thiol compound N-acetylcysteine (NAC), which may affect NTG responsiveness, was also studied. METHODS Nitrate tolerance was induced by a 72-h intravenous infusion of NTG and confirmed by a 65-68% reduction in the hypotensive response to NTG (P < 0.05). The hypotensive effects of acetylcholine (ACh) and sodium nitroprusside, (SNP) and possible NAC-mediated changes in the responses to these compounds were examined in nontolerant and nitrate-tolerant rats. Furthermore, the hypertensive response to the NO synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME) was measured. RESULTS Nitrate tolerance was associated with a significantly attenuated hypotensive response to ACh (before 24 +/- 1 mmHg; after 17 +/- 2 mmHg, n = 7, P < 0.05). Similarly, the response to SNP was reduced from 32 +/- 1 mmHg to 26 +/- 3 mmHg (n = 7, P < 0.05). NTG-vehicle (placebo) did not affect the response to ACh and SNP (P > 0.05). NAC augmented the effect of NTG, ACh and SNP in both nontolerant and nitrate-tolerant animals (P < 0.05). The hypertensive response to L-NAME (n = 8), was reduced by 67% (from 34 +/- 6 mmHg to 11 +/- 1 mmHg, P < 0.05) after induction of nitrate tolerance. CONCLUSIONS The results suggest (1) that nitrate tolerance in vivo is associated with cross tolerance to NO-mediated vasodilation produced by both exogenous and endogenous nitrovasodilators and (2) that also responses to nitrovasodilator agents other than NTG are improved by the addition of NAC.

Central and Peripheral Blood Flow During Exercise With a Continuous-Flow Left Ventricular Assist DeviceClinical Perspective

Background— End-stage heart failure is associated with impaired cardiac output (CO) and organ blood flow. We determined whether CO and peripheral perfusion are maintained during exercise in patients with an axial-flow left ventricular assist device (LVAD) and whether an increase in LVAD pump speed with work rate would increase organ blood flow. Methods and Results— Invasively determined CO and leg blood flow and Doppler-determined cerebral perfusion were measured during 2 incremental cycle exercise tests on the same day in 8 patients provided with a HeartMate II LVAD. In random order, patients exercised both with a constant (≈9775 rpm) and with an increasing pump speed (+400 rpm per exercise stage). At 60 W, the elevation in CO was more pronounced with increased pump speed (8.7±0.6 versus 8.1±1.1 L · min−1; mean±SD; P=0.05), but at maximal exercise increases in CO (from 7.0±0.9 to 13.6±2.5 L · min−1; P<0.01) and leg blood flow [0.7 (0.5 to 0.8) to 4.4 (3.9 to 4.8) L · min−1 per leg; median (range); P<0.001] were similar with both pumping modes. Normally, middle cerebral artery mean flow velocity increases from ≈50 to ≈65 cm · s−1 during exercise, but in LVAD patients with a constant pump speed it was low at rest (39±14 cm · s−1) and remained unchanged during exercise, whereas in patients with increasing pump speed, it increased by 5.2±2.8 cm · s−1 at 60 W (P<0.01). Conclusions— With maximal exercise, the axial-flow LVAD supports near-normal increments in cardiac output and leg perfusion, but cerebral perfusion is poor. Increased pump speed augments cerebral perfusion during exercise.