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.).

Esmolol for cardioprotection during resuscitation with adrenaline in an ischaemic porcine cardiac arrest model.

BACKGROUND: The effectiveness of adrenaline during resuscitation continues to be debated despite being recommended in international guidelines. There is evidence that the ß-adrenergic receptor (AR) effects of adrenaline are harmful due to increased myocardial oxygen consumption, post-defibrillation ventricular arrhythmias and increased severity of post-arrest myocardial dysfunction. Esmolol may counteract these unfavourable ß-AR effects and thus preserve post-arrest myocardial function. We evaluated whether a single dose of esmolol administered prior to adrenaline preserves post-arrest cardiac output among successfully resuscitated animals in a novel, ischaemic cardiac arrest porcine model. METHODS: Myocardial infarction was induced in 20 anaesthetized pigs by inflating a percutaneous coronary intervention (PCI) balloon in the circumflex artery 15 min prior to induction of ventricular fibrillation. After 10 min of untreated VF, resuscitation with veno-arterial extracorporeal membrane oxygenation (VA-ECMO) was initiated and the animals were randomized to receive an injection of either 1 mg/kg esmolol or 9 mg/ml NaCl, prior to adrenaline. Investigators were blinded to allocation. Successful defibrillation was followed by a 1-h high-flow VA-ECMO before weaning and an additional 1-h stabilization period. The PCI-balloon was deflated 40 min after inflation. Cardiac function pre- and post-arrest (including cardiac output) was assessed by magnetic resonance imaging (MRI) and invasive pressure measurements. Myocardial injury was estimated with MRI, triphenyl tetrazolium chloride (TTC) staining and serum concentrations of cardiac troponin T. RESULTS: Only seven esmolol and five placebo-treated pigs were successfully resuscitated and available for post-arrest measurements (p = 0.7). MRI revealed severe but similar reductions in post-arrest cardiac function with cardiac output 3.5 (3.3, 3.7) and 3.3 (3.2, 3.9) l/min for esmolol and control (placebo) groups, respectively (p = 0.7). The control group had larger left ventricular end-systolic and end-diastolic ventricular volumes compared to the esmolol group (75 (65, 100) vs. 62 (53, 70) ml, p = 0.03 and 103 (86, 124) vs. 87 (72, 91) ml, p = 0.03 for control and esmolol groups, respectively). There were no other significant differences in MRI characteristics, myocardial infarct size or other haemodynamic measurements between the two groups. CONCLUSIONS: We observed similar post-arrest cardiac output with and without a single dose of esmolol prior to adrenaline administration during low-flow VA-ECMO in an ischaemic cardiac arrest pig model.

Sepsis causes right ventricular myocardial inflammation independent of pulmonary hypertension in a porcine sepsis model.

INTRODUCTION: Right ventricular (RV) myocardial dysfunction is a common feature in septic shock. It can worsen outcome, but the etiology is poorly understood. Pulmonary artery hypertension (PAH) plays a part in the pathogenesis of the right heart dysfunction in sepsis but its importance is unknown. In pigs, PAH in sepsis is substantial and the translational value of porcine sepsis models therefore questioned. We hypothesized that porcine sepsis causes a myocardial inflammatory response which leads to myocardial dysfunction independent of PAH. MATERIALS AND METHODS: Sepsis was induced by Escherichia coli-infusion in 10 pigs resulting in PAH and increased right ventricular pressure (RVP). The same degree of RVP was achieved by external pulmonary artery banding (PAB) in a consecutive series of 6 animals. RESULTS: Sepsis, but not PAB, led to increase in endothelial damage marker PAI-1 and cytokines TNF and IL-6 (all p<0.05) in plasma. In myocardium, TNF and IL-6 were significantly elevated in sepsis, TNF in both ventricles and IL-6 mostly in RV, while IL-1ß, IL-18 and C5a were significantly higher in RV compared to LV after PAB (all p<0.05). Myocardial mRNA levels of IL-1ß, IL-6, IL-18, IP-10, E-selectin and PAI-1 were significantly elevated in RV and LV during sepsis compared to PAB, while Caspase-1 was decreased in septic compared to PAB animals (all p<0.05). Cathepsin L activity was increased in RV by PAB, while sepsis inhibited this response. Escherichia coli-induced sepsis caused myocardial inflammation independent of PAH. CONCLUSION: Prominent PAH should therefore not exclude porcine sepsis models to further our understanding of human sepsis.

Measurement of skin conductance responses to evaluate procedural pain in the perioperative setting.

Background and aims The subjective nature of pain makes objective, quantitative measurements challenging. The current gold standard for evaluating pain is patient self-reporting using the numeric rating scale (NRS) or Visual Analog Scale. Skin conductance responses per second (SCR) measured in the palmar region reflect the emotional part of the autonomous nervous system. SCR ≥0.20 have been shown to indicate moderate or severe pain in the postoperative setting. We examined whether SCR can detect procedure-related pain before major surgery. Methods In 20 patients being prepared for major surgery SCR was recorded before and during arterial cannulation, after induction of anaesthesia, and on the first postoperative day. Self-reported pain was evaluated using NRS. NRS >3 was considered to represent moderate or severe pain. Results NRS was 0 [0-0] before arterial cannulation, increasing to 5 [3-6] during arterial cannulation (p<0.05). Before arterial cannulation SCR was 0.27 [0.20-0.27], increasing to 0.33 [0.30-0.37] during arterial cannulation (p<0.01). On the first postoperative day both SCR and reported pain indicated no more than mild pain, SCR 0.13 [0.00-0.20] and NRS 2.0 [0.5-2.0]. The sensitivity of SCR to indicate moderate or severe pain (NRS >3) was 0.93 (0.68-1.0) and specificity was 0.33 (0.25-0.35) when the cut-off established in the postoperative setting (SCR ≥0.20) was used on all data. Conclusions SCR increased during arterial cannulation. Before major surgery the SCR was above the threshold demonstrated to indicate pain in the postoperative setting, even without painful stimuli and no reported pain. Using the threshold established for postoperative pain, SCR cannot reliably discriminate between pain and other stressors before major surgery. Implications Before major surgery, the diagnosis of moderate or severe pain should not be made based on SCR ≥0.20.

Intraoperative improvement in left ventricular peak systolic velocity predicts better short-term outcome after transcatheter aortic valve implantation.

OBJECTIVES: Left ventricular function is expected to improve after transcatheter aortic valve implantation due to the acute reduction in afterload, but does not occur in all patients. We hypothesized that the immediate intraoperative response in systolic left ventricular longitudinal motion during the procedure could be a predictor of short-term outcome. METHODS: Sixty-four patients treated with transcatheter aortic valve implantation for severe aortic stenosis were included. Transoesophageal 4- and 2-chamber echocardiograms were obtained immediately prior to and ∼15 min after valve implantation. Patients were defined as responders if their average left ventricular longitudinal peak systolic velocity increased by ≥20% from the preimplantation value and was related to the 3-month outcome. RESULTS: Thirty-five patients were classified as responders, with an increase in the intraoperative longitudinal peak systolic velocity from an average of 2.2 ± 0.8 to 3.1 ± 1.1 cm/s (P < 0.001); the velocity was unchanged in the remaining 29 patients, who averaged 2.4 ± 1.1 cm/s. There were significantly fewer adverse cardiac events in the responder group at the 3-month follow-up (20 vs 45%, P = 0.03) and the New York Heart Association class was significantly better in the responders compared with non-responders. Responders had a significant reduction in N-terminal probrain natriuretic peptide levels [243 (113-361) vs 163 (64-273), P = 0.004] at the 3-month follow-up, whereas non-responders did not [469 (130-858) vs 289 (157-921), P = 0.48]. CONCLUSIONS: An immediate improvement in the longitudinal peak systolic velocity during the transcatheter aortic valve implantation procedure predicted a better short-term outcome and may be useful in identifying patients who are at risk of a less favourable outcome after transcatheter aortic valve implantation.

A low body temperature on arrival at hospital following out-of-hospital-cardiac-arrest is associated with increased mortality in the TTM-study.

AIM: To investigate the association of temperature on arrival to hospital after out-of-hospital-cardiac arrest (OHCA) with the primary outcome of mortality, in the targeted temperature management (TTM) trial. METHODS: The TTM trial randomized 939 patients to TTM at 33 or 36°C for 24h. Patients were categorized according to their recorded body temperature on arrival and also categorized to groups of patients being actively cooled or passively rewarmed. RESULTS: OHCA patients having a temperature ≤34.0°C on arrival at hospital had a significantly higher mortality compared to the OHCA patients with a higher temperature on arrival. A low body temperature on arrival was associated with a longer time to return of spontaneous circulation (ROSC) and duration of transport time to hospital. Patients who were actively cooled or passively rewarmed during the first 4h had similar mortality. In a multivariate logistic regression model mortality was significantly related to time from OHCA to ROSC, time from OHCA to advanced life support (ALS), age, sex and first registered rhythm. None of the temperature related variables (included the TTM-groups) were significantly related to mortality. CONCLUSION: OHCA patients with a temperature ≤34.0°C on arrival have a higher mortality than patients with a temperature ≥34.1°C on arrival. A low temperature on arrival is associated with a long time to ROSC. Temperature changes and TTM-groups were not associated with mortality in a regression model.

Successful ECMO-cardiopulmonary resuscitation with the associated post-arrest cardiac dysfunction as demonstrated by MRI.

BACKGROUND: Veno-arterial extracorporeal membrane oxygenation (ECMO-CPR) is a life-saving rescue for selected patients when standard cardiopulmonary resuscitation fails. The use is increasing although the treatment modality is not fully established. Resuscitated patients typically develop a detrimental early post-arrest cardiac dysfunction that also deserves main emphasis. The present study investigates an ECMO-CPR strategy in pigs and assesses early post-arrest left ventricular function in detail. We hypothesised that a significant dysfunction could be demonstrated with this model using magnetic resonance imaging (MRI), not previously used early post-arrest. METHODS: In eight anaesthetised pigs, a 15-min ventricular fibrillation was resuscitated by an ECMO-CPR strategy of 150-min veno-arterial ECMO aiming at high blood flow rate and pharmacologically sustained aortic blood pressure and pulse pressure of 50 and 15 mmHg, respectively. Pre-arrest cardiac MRI and haemodynamic measurements of left ventricular function were compared to measurements performed 300-min post-arrest. RESULTS: All animals were successfully resuscitated, weaned from the ECMO circuit, and haemodynamically stabilised post-arrest. Cardiac output was maintained by an increased heart rate post-arrest, but left ventricular ejection fraction and stroke volume were decreased by approximately 50 %. Systolic circumferential strain and mitral annular plane systolic excursion as well as the left ventricular wall thickening were reduced by approximately 50-70 % post-arrest. The diastolic function variables measured were unchanged. CONCLUSIONS: The present animal study demonstrates a successful ECMO-CPR strategy resuscitating long-lasting cardiac arrest with adequate post-arrest haemodynamic stability. The associated severe systolic left ventricular dysfunction could be charted in detail by MRI, a valuable tool for future cardiac outcome assessments in resuscitation research. TRIAL REGISTRATION: Institutional protocol number: FOTS 4611/13 .

Systolic left ventricular function is preserved during therapeutic hypothermia, also during increases in heart rate with impaired diastolic filling.

BACKGROUND: Systolic left ventricular function during therapeutic hypothermia is found both to improve and to decline. We hypothesized that this discrepancy would depend on the heart rate and the variables used to assess systolic function. METHODS: In 16 pigs, cardiac performance was assessed by measurements of invasive pressures and thermodilution cardiac output and with 2D strain echocardiography. Left ventricle (LV) volumes, ejection fraction (EF), transmitral flow, and circumferential and longitudinal systolic strain were measured. Miniaturized ultrasonic transducers were attached to the epicardium of the LV to obtain M-mode images, systolic thickening, and diastolic thinning velocities and to determine LV pressure-wall dimension relationships. Preload recruitable stroke work (PRSW) was calculated. Measurements were performed at 38 and 33°C at spontaneous and paced heart rates, successively increased in steps of 20 up to the toleration limit. Effects of temperature and heart rate were compared in a mixed model analysis. RESULTS: Hypothermia reduced heart rate from 87 ± 10 (SD) to 76 ± 11 beats/min without any changes in LV stroke volume, end-diastolic volume, EF, strain values, or PRSW. Systolic wall thickening velocity (S') and early diastolic wall thinning velocity decreased by approximately 30%, making systolic duration longer through a prolonged and slow contraction and changing the diastolic filling pattern from predominantly early towards late. Pacing reduced diastolic duration much more during hypo- than during normothermia, and combined with slow myocardial relaxation, incomplete relaxation occurred with all pacing rates. Pacing did not affect S' or PRSW at physiological heart rates, but stroke volume, end-diastolic volume, and strain were reduced as a consequence of reduced diastolic filling and much more accentuated during hypothermia. At the ultimate tolerable heart rate during hypothermia, S' decreased, probably as a consequence of myocardial hypoperfusion due to sustained ventricular contraction throughout a very short diastole. CONCLUSIONS: Systolic function was maintained at physiological heart rates during therapeutic hypothermia. Reduced tolerance to increases in heart rate was caused by lack of ventricular filling due to diastolic dysfunction and shorter diastolic duration.

Influence of renal replacement therapy on pharmacokinetics in critically ill patients.

Critical illness has a great impact on many pharmacokinetic parameters. An increased volume of distribution often results in drug underdosing, whereas organ impairment may lead to drug accumulation and overdosing. Renal replacement therapy (RRT) in critically ill patients with renal failure may significantly increase drug clearance, requiring drug-dosing adjustments. Drugs significantly eliminated by the kidney are likely to experience substantial removal during RRT, and a supplemental dose--corresponding to the amount of drug removed by RRT--should be administered. Mechanisms of drug removal during RRT are reviewed together with methods for measuring or estimating RRT drug clearances. Approaches for drug-dosing adjustments are suggested and, at the end, the pharmacological principles for antibiotic prescription in the critically ill are discussed.