Jürgen Knapp

The First Shot Is Often the Best Shot: First-Pass Intubation Success in Emergency Airway Management.

November 2015 • Volume 121 • Number 5 www.anesthesia-analgesia.org 1389 Copyright

Pre- and postconditioning effect of Sevoflurane on myocardial dysfunction after cardiopulmonary resuscitation in rats.

Post-resuscitation myocardial dysfunction is an important cause of death in the intensive care unit after initially successful cardiopulmonary resuscitation (CPR) of pre-hospital cardiac arrest (CA) patients. Volatile anaesthetics reduce ischaemic-reperfusion injury in regional ischaemia in beating hearts. This effect, called anaesthetic-induced pre- or postconditioning, can be shown when the volatile anaesthetic is given either before regional ischaemia or in the reperfusion phase. However, up to now, little data exist for volatile anaesthetics after global ischaemia due to CA. Therefore, the goal of this study was to clarify whether Sevoflurane improves post-resuscitation myocardial dysfunction after CA in rats. Following institutional approval by the Governmental Animal Care Committee, 144 male Wistar rats (341±19g) were randomized either to a control group or to one of the 9 interventional groups receiving 0.25 MAC, 0.5 MAC or 1 MAC of Sevoflurane for 5min either before resuscitation (SBR), during resuscitation (SDR) or after resuscitation (SAR). After 6min of electrically induced ventricular fibrillation CPR was performed. Before CA (baseline) as well as 1h and 24h after restoration of spontaneous circulation (ROSC), continuous measurement of ejection fraction (EF), and preload adjusted maximum power (PAMP) as primary outcome parameters and end systolic pressure (ESP), end diastolic volume (EDV) and maximal slope of systolic pressure increment (dP/dtmax) as secondary outcome parameters was performed using a conductance catheter. EF was improved in all Sevoflurane treated groups 1h after ROSC in comparison to control, except for the 0.25 MAC SDR and 0.25 MAC SAR group (0.25 MAC SBR: 38±8, p=0.02; 0.5 MAC SBR: 39±7, p=0.04; 1 MAC SBR: 40±6, p=0.007; 0.5 MAC SDR: 38±7, p=0.02; 1 MAC SDR: 40±6, p=0.006; 0.5 MAC SAR: 39±6, p=0.01; 1 MAC SAR: 39±6, p=0.002, vs. 30±7%). Twenty-four hours after ROSC, EF was higher than control in all interventional groups (p<0.05 for all groups). EF recovered to baseline values 24h after ROSC in all SBR and SAR groups. PAMP was improved in comparison to control (4.6±3.0mW/μl(2)) 24h after ROSC in 0.5 MAC SBR (9.4±6.9mW/μl(2), p=0.04), 1 MAC SBR (8.9±4.4mW/μl(2), p=0.04), 1 MAC SDR (8.0±5.7mW/μl(2), p=0.04), and 1 MAC SAR (7.3±3.5mW/μl(2), p=0.04). ESP, EDV, and dP/dtmax was not different from control 1h as well as 24h after ROSC with the exception of 1 MAC SDR with a reduced ESP 1h after ROSC (89±16 vs. 103±22mmHg, p=0.04). Sevoflurane treatment did not affect survival rate. This animal study of CA and resuscitation provides the hypothesis that pharmacological pre- or postconditioning with the volatile anaesthetic Sevoflurane - administered before CA, during resuscitation or after ROSC - results in an improved myocardial inotropy 24h after ROSC. Sevoflurane treatment seems to improve EF even in the early phase of reperfusion 1h after ROSC. Therefore further targeted studies on the optimal dose and time point of administration of Sevoflurane in cardiopulmonary resuscitation seem to be worthwhile (Institutional protocol number: 35-9185.81/G-24/08).

Hypothermia and neuroprotection by sulfide after cardiac arrest and cardiopulmonary resuscitation.

BACKGROUND Poor neurological outcome remains a major problem in patients suffering cardiac arrest. Recent data have demonstrated potent neuroprotective effects of the administration of sulfide donor compounds after ischaemia/reperfusion injury following cardiac arrest and resuscitation. Therefore, we sought to evaluate the impact of sodium sulfide (Na(2)S), a liquid hydrogen sulfide donor on core body temperature and neurological outcome after cardiac arrest in rats. METHODS Fifty male Wistar rats were randomized into two groups (sulfide vs. placebo, n=25 per group). Cardiac arrest was induced by transoesophageal ventricular fibrillation during general anaesthesia. After 6 min of global cerebral ischaemia, animals were resuscitated by external chest compressions combined with defibrillation. An investigator blinded bolus of either Na(2)S (0.5 mg/kg body weight) or placebo 1 min before the beginning of CPR, followed by a continuous infusion of Na(2)S (1 mg/kg body weight/h) or placebo for 6 h, was administered intravenously. 1 day, 3 days, and 7 days after restoration of spontaneous circulation, neurological outcome was evaluated by a tape removal test. After 7 days of reperfusion, coronal brain sections were analyzed by TUNEL- and Nissl-staining. A caspase activity assay was used to determine antiapoptotic properties of Na(2)S. RESULTS Temperature course was similar in both groups (mean minimal temperature in the sulfide group 31.3±1.2°C vs. 30.8±1.9°C in the placebo group; p=0.29). Despite significant neuroprotection demonstrated by the tape removal test after 3 days of reperfusion in the sulfide treated group, there was no significant difference in neuronal survival at day 7. Likewise results from TUNEL-staining revealed no differences in the amount of apoptotic cell death between the groups after 7 days of reperfusion. CONCLUSION In our rat model of cardiac arrest, sulfide therapy was associated with only a short term beneficial effect on neurological outcome.

Evaluation of cyclosporine a as a cardio- and neuroprotective agent after cardiopulmonary resuscitation in a rat model.

ABSTRACT The immunosuppressant drug cyclosporine A (CsA) is a direct inhibitor of the mitochondrial permeability transition pore, which is the common end point of many pathways of ischemic preconditioning and postconditioning. We studied the neuroprotective and cardioprotective effect of CsA after cardiac arrest (CA) in a rat model of cardiopulmonary resuscitation. After institutional approval by the Governmental Animal Care Committee, 83 rats were subjected to 6 min of CA and were randomly and investigator-blinded allocated either to placebo (n = 15) or interventional group (n = 15; 10-mg/kg body weight CsA intravenously) after restoration of spontaneous circulation (ROSC). Before CA (baseline) as well as 1 h and 3 h after ROSC, continuous measurement of stroke volume, left ventricular ejection fraction, preload adjusted maximum power, and end diastolic volume was performed using a conductance catheter. One day, 3 days, and 7 days after ROSC, neurological outcome was evaluated by a tape removal test. After 7 days of reperfusion, coronal brain sections were analyzed by counting Nissl-positive (i.e., viable) neurons and terminal deoxynucleotidyl transferase dUTP nick end labeling positive (i.e., apoptotic) cells. Animals treated with CsA had a higher stroke volume (96 [93; 107] &mgr;L vs. 78 [73; 94] &mgr;L; P = 0.02), higher ejection fraction (58% [51%; 63%] vs. 42% [35%; 51%]; P = 0.002), and higher preload adjusted maximum power (4.8 [3.9; 6.1] vs. 2.3 [2.0; 2.6] mW/&mgr;L2; P < 0.001). End diastolic volume remained stable in the CsA group 3 h after ROSC in comparison to baseline (160 [143; 181] &mgr;L vs. 157 [148; 192] &mgr;L; P = 0.56), whereas it increased in the placebo group (169 [153; 221] &mgr;L vs. 156 [138; 166] &mgr;L, P = 0.05). More neurons survived after administration of CsA (2.5 [1.6; 4.9] vs. 0.7 [0.4; 1.4]; P = 0.005). Compared to placebo-treated animals, the time in the tape removal test 7 days after ROSC was reduced by half in the CsA group without reaching statistical significance (26 [22; 51] vs. placebo 53 [38; 56] s; P = 0.13). Cyclosporine A treatment neither affected the number of terminal deoxynucleotidyl transferase dUTP nick end labeling–positive cells nor the survival rate. Pharmacological postconditioning with CsA after successful cardiopulmonary resuscitation attenuates myocardial dysfunction and reduces neuronal damage.

Time-course of plasma inflammatory mediators in a rat model of brain death

BACKGROUND Brain death (BD) is a donor-associated risk factor that negatively affects transplantation outcome. The inflammation associated with BD appears to have a negative effect on organ quality. Complement activation, apoptosis, and pro-inflammatory cytokine and chemokine expression are significantly increased after BD. To better understand this process, we investigated plasma chemokine and cytokine levels for 8h after BD in a rodent model. METHODS Thirteen healthy adult male Sprague Dawley rats were intubated and mechanically ventilated. After induction of BD, animals were kept hemodynamically stable for 8h. A panel of immune response factors, including cytokines and chemokines, were measured immediately prior to the induction of BD and at 1, 4, and 8h after BD by multiplex analyses in 10 rats. RESULTS In the early phase of BD, we observed an increase in heart rate and a decrease in mean arterial pressure. Only limited fluctuations were noted in the partial pressure of O2, O2 saturation, and HCO3. Monocyte-/macrophage- and lymphocyte-derived mediators (IL-2, IL-4, and IFN-γ) increased steadily during the 8-hour monitoring period. CONCLUSIONS The increase in immune responses, particularly pro-inflammatory responses, after BD is time-dependent. Cytokines and chemokines from donors and recipients require further investigation to determine the optimal time frames for organ transplantation in rodent models and humans.

Effects of intracerebroventricular application of insulin-like growth factor 1 and its N-terminal tripeptide on cerebral recovery following cardiac arrest in rats

BACKGROUND Following global cerebral ischaemia due to cardiac arrest (CA), selective neuronal vulnerability and delayed neuronal death with distinct signs of apoptosis could be observed in certain areas of the brain. Growth hormones like the insulin-like growth factor 1 (IGF-1) and the bioactive N-terminal tripeptide of IGF-1, glycine-proline-glutamate (GPE), exhibit strong protective properties in focal ischaemia in vivo and in vitro. To examine these promising effects on neuronal survival and cerebral recovery after experimental cardiopulmonary resuscitation, the most vulnerable hippocampal CA-1 sector was investigated. METHODS After 6 min of CA, 54 male Wistar rats were resuscitated and were randomly assigned to 3 groups (IGF-1, GPE vs. placebo; n=6 per group) and 3 different reperfusion periods. Intracerebroventricular application of IGF-1 (1.25 μgh(-1)), GPE (50 ngh(-1)) and placebo was performed using osmotic minipumps up to day 7 following reperfusion. After 3, 7 and 14 days, coronal brain sections were analysed by counting Nissl-positive (i.e. viable) neurons and TUNEL-positive (i.e., apoptotic) cells. All experiments were performed in a randomised and blinded setting. RESULTS In all groups in the hippocampal CA-1 sector typical delayed neurodegeneration from day 3 to day 14 after CA could be found. No significant increase of the number of Nissl-positive neurons after IGF-1-treatment (p=0.18) as well as after GPE-treatment (p=0.14) could be observed. The number of TUNEL-positive cells could not be reduced significantly in the IGF-1 group (p=0.13), whereas GPE treatment revealed significant less TUNEL-positive cells (p=0.02). This was primarily an effect in the early phase (day 3: p=0.02) of reperfusion and was no more detectable 7 days (p=0.69) and 14 days after ROSC (p=0.30). CONCLUSION Despite the well known neuroprotective properties of IGF-1 and GPE in ischaemic induced neuronal degeneration, this model could only reveal a short-term beneficial effect of GPE after experimental cardiac arrest in rats. (Institutional protocol number: 35-9185.81/43/00.).

Cardiac Arrest/Code

It is not known how many patients suffer cardiocirculatory arrest and need to be resuscitated while in the hospital. However, we do know that fewer than 20% of patients who suffer cardiocirculatory arrest in the hospital survive and leave the clinic again. We also know that during and around surgery 2 out of 1,000 patients develop myocardial infarction – which is one of the most important causes of cardiocirculatory arrest (Table 41.1). For major surgery or surgery associated with a high loss of blood, the risk of cardiovascular complications is as high as 2%. Successful cardiopulmonary resuscitation (CPR) requires intensive practical instruction and training and good teamwork as well.