Oxygenation and ventilation during prolonged experimental cardiopulmonary resuscitation with either continuous or 30:2 compression-to-ventilation ratios together with 10 cmH20 positive end-expiratory pressure.

BACKGROUND: In refractory out-of-hospital cardiac arrest, the patient is commonly transported to hospital with mechanical continuous chest compressions (CCC). Limited data are available on the optimal ventilation strategy. Accordingly, we compared arterial oxygenation and haemodynamics during manual asynchronous continuous ventilation and compressions with a 30:2 compression-to-ventilation ratio together with the use of 10 cmH2O positive end-expiratory pressure (PEEP). METHODS: Intubated and anaesthetized landrace pigs with electrically induced ventricular fibrillation were left untreated for 5 min (n = 31, weight ca. 55 kg), after which they were randomized to either the CCC group or the 30:2 group with the the LUCAS® 2 piston device and bag-valve ventilation with 100% oxygen targeting a tidal volume of 8 ml/kg with a PEEP of 10 cmH2O for 35 min. Arterial blood samples were analysed every 5 min, vital signs, near-infrared spectroscopy and electrical impedance tomography (EIT) were measured continuously, and post-mortem CT scans of the lungs were obtained. RESULTS: The arterial blood values (median + interquartile range) at the 30-min time point were as follows: PaO2: 180 (86-302) mmHg for the 30:2 group; 70 (49-358) mmHg for the CCC group; PaCO2: 41 (29-53) mmHg for the 30:2 group; 44 (21-67) mmHg for the CCC group; and lactate: 12.8 (10.4-15.5) mmol/l for the 30:2 group; 14.7 (11.8-16.1) mmol/l for the CCC group. The differences were not statistically significant. In linear mixed models, there were no significant differences between the groups. The mean arterial pressures from the femoral artery, end-tidal CO2, distributions of ventilation from EIT and mean aeration of lung tissue in post-mortem CTs were similar between the groups. Eight pneumothoraces occurred in the CCC group and 2 in the 30:2 group, a statistically significant difference (p = 0.04). CONCLUSIONS: The 30:2 and CCC protocols with a PEEP of 10 cmH2O resulted in similar gas exchange and vital sign outcomes in an experimental model of prolonged cardiac arrest with mechanical compressions, but the CCC protocol resulted in more post-mortem pneumothoraces.

Bilateral Superficial Trigeminal Nerve Blocks are not More Effective than a Placebo in Abolishing Post-operative Headache Pain in Pituitary Transsphenoidal Neurosurgery: A Prospective, Randomized, Doubleblinded Clinical Trial.

BACKGROUND: Pituitary neurosurgery executed via the transsphenoidal endonasal approach is commonly performed for pituitary adenomas. Reasons for prolonged hospital stay include postoperative headache and protracted nausea with or without vomiting. Bilateral superficial trigeminal nerve blocks of the supra-orbital V1 and infra-orbital V2 (SION) nerves performed intra-operatively as a regional anesthetic adjunct to general anesthesia were hypothesized to decrease 6 hours postoperative morphine PCA (patient-controlled analgesia) use by patients. METHODS: Forty-nine patients, following induction of general anesthesia for their transsphenoidal surgery, were prospectively randomized in a double-blinded fashion to receive additional regional anesthesia as either a block (0.5% ropivacaine with epi 1:200,000) or placebo/sham (0.9% normal saline). The primary endpoint of the study was systemic morphine PCA opioid consumption by the two groups in the first 6-hours postoperatively. The secondary endpoints included (1) pain exposure experienced postoperatively, (2) incidence of postoperative nausea and vomiting, and (3) time to eligibility for PACU discharge. RESULTS: Of the 49 patients that were enrolled, 3 patients were excluded due to protocol violations. Ultimately, there was no statistically significant difference between morphine PCA use in the 6 hours postoperatively between the block and placebo/sham groups. There was, however, a slight visual tendency in the block group for higher pain scores, morphine use p=0.046, and delayed PACU discharge. False discovery rate corrected comparisons at each time point and then revealed no statistically significant difference between the two groups. There were no differences between the two groups for secondary endpoints. CONCLUSION: It was found that a 6-hour postoperative headache after endoscopic trans-sphenoidal pituitary surgery likely has a more complicated mechanism involving more than the superficial trigeminovascular system and perhaps is neuro-modulated by other brain nuclei.

Ventilation during continuous compressions or at 30:2 compression-to-ventilation ratio results in similar arterial oxygen and carbon dioxide levels in an experimental model of prolonged cardiac arrest.

BACKGROUND: In refractory out-of-hospital cardiac arrest, transportation to hospital with continuous chest compressions (CCC) from a chest compression device and ventilation with 100% oxygen through an advanced airway is common practice. Despite this, many patients are hypoxic and hypercapnic on arrival, possibly related to suboptimal ventilation due to the counterpressure caused by the CCC. We hypothesized that a compression/ventilation ratio of 30:2 would provide better ventilation and gas exchange compared to asynchronous CCC during prolonged experimental cardiopulmonary resuscitation (CPR). METHODS: We randomized 30 anaesthetized domestic swine (weight approximately 50 kg) with electrically induced ventricular fibrillation to the CCC or 30:2 group and bag-valve ventilation with a fraction of inspired oxygen (FiO2) of 100%. We started CPR after a 5-min no-flow period and continued until 40 min from the induction of ventricular fibrillation. Chest compressions were performed with a Stryker Medical LUCAS® 2 mechanical chest compression device. We collected arterial blood gas samples every 5 min during the CPR, measured ventilation distribution during the CPR using electrical impedance tomography (EIT) and analysed post-mortem computed tomography (CT) scans for differences in lung aeration status. RESULTS: The median (interquartile range [IQR]) partial pressure of oxygen (PaO2) at 30 min was 110 (52-117) mmHg for the 30:2 group and 70 (40-171) mmHg for the CCC group. The median (IQR) partial pressure of carbon dioxide (PaCO2) at 30 min was 70 (45-85) mmHg for the 30:2 group and 68 (42-84) mmHg for the CCC group. No statistically significant differences between the groups in PaO2 (p = 0.40), PaCO2 (p = 0.79), lactate (p = 0.37), mean arterial pressure (MAP) (p = 0.47) or EtCO2 (p = 0.19) analysed with a linear mixed model were found. We found a deteriorating trend in PaO2, EtCO2 and MAP and rising PaCO2 and lactate levels through the intervention. There were no differences between the groups in the distribution of ventilation in the EIT data or the post-mortem CT findings. CONCLUSIONS: The 30:2 and CCC protocols resulted in similar gas exchange and lung pathology in an experimental prolonged mechanical CPR model.

The use of 100% compared to 50% oxygen during ineffective experimental cardiopulmonary resuscitation improves brain oxygenation.

INTRODUCTION: Perfusion pressure and chest compression quality are generally considered key determinants of brain oxygenation during cardiopulmonary resuscitation (CPR) and the impact of oxygen administration is less clear. We compared ventilation with 100% and 50% oxygen during ineffective manual chest compressions and hypothesized that 100% oxygen would improve brain oxygenation. METHODS: Ventricular fibrillation (VF) was induced electrically in anaesthetized pigs and left untreated for 5 minutes, followed by randomization to ineffective manual CPR with ventilation of 50% or 100% oxygen. The first defibrillation was performed 10 minutes after induction of VF, and CPR continued with mechanical chest compressions (LUCAS2™) and defibrillation every 2 minutes until 36 minutes or return of spontaneous circulation (ROSC). Brain oxygenation was measured with near-infrared spectroscopy (rSO2) and invasive brain tissue oxygen (PbtO2) with a probe (NEUROVENT-PTO, RAUMEDIC) inserted into frontal brain tissue. Cerebral oxygenation was compared between groups with Mann-Whitney U tests and linear mixed models. RESULTS: Twenty-eight pigs were included in the study: 14 subjects in each group. During ineffective chest compressions relative PbtO2 was higher in the group ventilated with 100% compared to 50% oxygen (5.2 mmHg [1.4-20.5] vs 2.2 [0.8-6.8], p = 0.001), but there was no difference in rSO2 (22% [16-28] vs 18 [15-25], p = 0.090). The use of 50% or 100% oxygen showed no difference in relative PbtO2 (p = 1.00) and rSO2 (p = 0.206) during mechanical CPR. CONCLUSIONS: The use of 100% compared to 50% oxygen during ineffective manual CPR improved brain oxygenation measured invasively in brain tissue, but there was no difference in rSO2.

High Oxygen Does Not Increase Reperfusion Injury Assessed with Lipid Peroxidation Biomarkers after Cardiac Arrest: A Post Hoc Analysis of the COMACARE Trial.

The products of polyunsaturated fatty acid peroxidation are considered reliable biomarkers of oxidative injury in vivo. We investigated ischemia-reperfusion-related oxidative injury by determining the levels of lipid peroxidation biomarkers (isoprostane, isofuran, neuroprostane, and neurofuran) after cardiac arrest and tested the associations between the biomarkers and different arterial oxygen tensions (PaO2). We utilized blood samples collected during the COMACARE trial (NCT02698917). In the trial, 123 patients resuscitated from out-of-hospital cardiac arrest were treated with a 10-15 kPa or 20-25 kPa PaO2 target during the initial 36 h in the intensive care unit. We measured the biomarker levels at admission, and 24, 48, and 72 h thereafter. We compared biomarker levels in the intervention groups and in groups that differed in oxygen exposure prior to randomization. Blood samples for biomarker determination were available for 112 patients. All four biomarker levels peaked at 24 h; the increase appeared greater in younger patients and in patients without bystander-initiated life support. No association between the lipid peroxidation biomarkers and oxygen exposure either before or after randomization was found. Increases in the biomarker levels during the first 24 h in intensive care suggest continuing oxidative stress, but the clinical relevance of this remains unresolved.

Intensive care-treated cardiac arrest: a retrospective study on the impact of extended age on mortality, neurological outcome, received treatments and healthcare-associated costs.

BACKGROUND: Cardiac arrest (CA) is a leading cause of death worldwide. As population ages, the need for research focusing on CA in elderly increases. This study investigated treatment intensity, 12-month neurological outcome, mortality and healthcare-associated costs for patients aged over 75 years treated for CA in an intensive care unit (ICU) of a tertiary hospital. METHODS: This single-centre retrospective study included adult CA patients treated in a Finnish tertiary hospital's ICU between 2005 and 2013. We stratified the study population into two age groups: <75 and [Formula: see text]75 years. We compared interventions defined by the median daily therapeutic scoring system (TISS-76) between the age groups to find differences in treatment intensity. We calculated cost-effectiveness by dividing the total one-year healthcare-associated costs of all patients by the number of survivors with a favourable neurological outcome. Favourable outcome was defined as a cerebral performance category (CPC) of 1-2 at 12 months after cardiac arrest. Logistic regression analysis was used to identify independent associations between age group, mortality and neurological outcome. RESULTS: This study included a total of 1,285 patients, of which 212 (16 %) were [Formula: see text]75 years of age. Treatment intensity was lower for the elderly compared to the younger group, with median TISS scores of 116 and 147, respectively (p < 0.001). The effective cost in euros for patients with a good one-year neurological outcome was €168,000 for the elderly and €120,000 for the younger group. At 12 months after CA 24 % of the patients in the elderly group and 47 % of the patients in the younger group had a CPC of 1-2 (p < 0.001). Age was an independent predictor of mortality (multivariate OR = 2.90, 95 % CI: 1.94-4.31, p < 0.001) and neurological outcome (multivariate OR = 3.15, 95 % CI: 2.04-4.86, p < 0.001). CONCLUSIONS: The elderly ICU-treated CA patients in this study had worse neurological outcomes, higher mortality and lower cost-effectiveness than younger patients. Elderly received less intense treatment. Further efforts are needed to recognize the tools for assessing which elderly patients benefit from a more aggressive treatment approach in order to improve the cost-effectiveness of post-CA management.

The Association Between Arterial Oxygen Level and Outcome in Neurocritically Ill Patients is not Affected by Blood Pressure.

BACKGROUND: In neurocritically ill patients, one early mechanism behind secondary brain injury is low systemic blood pressure resulting in inadequate cerebral perfusion and consequent hypoxia. Intuitively, higher partial pressures of arterial oxygen (PaO2) could be protective in case of inadequate cerebral circulation related to hemodynamic instability. STUDY PURPOSE: We examined whether the association between PaO2 and mortality is different in patients with low compared to normal and high mean arterial pressure (MAP) in patients after various types of brain injury. METHODS: We screened the Finnish Intensive Care Consortium database for mechanically ventilated adult (≥ 18) brain injury patients treated in several tertiary intensive care units (ICUs) between 2003 and 2013. Admission diagnoses included traumatic brain injury, cardiac arrest, subarachnoid and intracranial hemorrhage, and acute ischemic stroke. The primary exposures of interest were PaO2 (recorded in connection with the lowest measured PaO2/fraction of inspired oxygen ratio) and the lowest MAP, recorded during the first 24 h in the ICU. PaO2 was grouped as follows: hypoxemia (< 8.2 kPa, the lowest 10th percentile), normoxemia (8.2-18.3 kPa), and hyperoxemia (> 18.3 kPa, the highest 10th percentile), and MAP was divided into equally sized tertiles (< 60, 60-68, and > 68 mmHg). The primary outcome was 1-year mortality. We tested the association between hyperoxemia, MAP, and mortality with a multivariable logistic regression model, including the PaO2, MAP, and interaction of PaO2*MAP, adjusting for age, admission diagnosis, premorbid physical performance, vasoactive use, intracranial pressure monitoring use, and disease severity. The relationship between predicted 1-year mortality and PaO2 was visualized with locally weighted scatterplot smoothing curves (Loess) for different MAP levels. RESULTS: From a total of 8290 patients, 3912 (47%) were dead at 1 year. PaO2 was not an independent predictor of mortality: the odds ratio (OR) for hyperoxemia was 1.16 (95% CI 0.85-1.59) and for hypoxemia 1.24 (95% CI 0.96-1.61) compared to normoxemia. Higher MAP predicted lower mortality: OR for MAP 60-68 mmHg was 0.73 (95% CI 0.64-0.84) and for MAP > 68 mmHg 0.80 (95% CI 0.69-0.92) compared to MAP < 60 mmHg. The interaction term PaO2*MAP was nonsignificant. In Loess visualization, the relationship between PaO2 and predicted mortality appeared similar in all MAP tertiles. CONCLUSIONS: During the first 24 h of ICU treatment in mechanically ventilated brain injured patients, the association between PaO2 and mortality was not different in patients with low compared to normal MAP.

Early hyperoxemia is not associated with cardiac arrest outcome.

AIM: Studies suggest that hyperoxemia increases short-term mortality after cardiopulmonary resuscitation (CPR), but the effect of hyperoxemia on long-term outcomes is unclear. We determined the prevalence of early hyperoxemia after CPR and its association with long-term neurological outcome and mortality. METHODS: We analysed data from adult cardiac arrest patients treated after CPR in tertiary ICUs during 2005-2013. We retrieved data from the resuscitation and the first arterial blood sample collected after return of spontaneous circulation (ROSC) (severe hyperoxemia defined as PaO2 > 40 kPa and moderate as PaO2 16-40 kPa). We inspected two outcomes, neurological performance at one year after resuscitation according to the Cerebral Performance Category and one-year mortality. We used logistic regression to test associations between hyperoxemia and the outcome and interaction analyses to test the effect of hyperoxemia exposure on the outcomes in smaller subgroups. RESULTS: Of 1110 patients 11% had severe hyperoxemia, prevalence was 10% for out-of-hospital arrests, 13% for in-hospital arrests and 9% for in-ICU arrests. In total 585(53%) patients had an unfavourable neurological outcome. Compared to normoxemia, severe (Odds ratio [OR] 0.81, 95% confidence interval [CI] 0.50-1.30) and moderate hyperoxemia (OR 0.94 95%CI 0.69-1.27) did not associate with neurological outcome. Additionally, hyperoxemia had no association with mortality. In subgroup analyses there were no significant associations between severe hyperoxemia and outcomes regardless of cardiac arrest location, initial rhythm or time-to-ROSC. CONCLUSION: We found no association between early post-arrest hyperoxemia and unfavourable outcome. Subgroup analysis found no differential effect depending on arrest location, initial rhythm or time-to-ROSC.

Association of extracerebral organ failure with 1-year survival and healthcare-associated costs after cardiac arrest: an observational database study.

BACKGROUND: Organ dysfunction is common after cardiac arrest and associated with worse short-term outcome, but its impact on long-term outcome and treatment costs is unknown. METHODS: We used nationwide registry data from the intensive care units (ICU) of the five Finnish university hospitals to evaluate the association of 24-h extracerebral Sequential Organ Failure Assessment (24h-EC-SOFA) score with 1-year survival and healthcare-associated costs after cardiac arrest. We included adult cardiac arrest patients treated in the participating ICUs between January 1, 2003, and December 31, 2013. We acquired the confirmed date of death from the Finnish Population Register Centre database and gross 1-year healthcare-associated costs from the hospital billing records and the database of the Finnish Social Insurance Institution. RESULTS: A total of 5814 patients were included in the study, and 2401 were alive 1 year after cardiac arrest. Median (interquartile range (IQR)) 24h-EC-SOFA score was 6 (5-8) in 1-year survivors and 7 (5-10) in non-survivors. In multivariate regression analysis, adjusting for age and prior independency in self-care, the 24h-EC-SOFA score had an odds ratio (OR) of 1.16 (95% confidence interval (CI) 1.14-1.18) per point for 1-year mortality. Median (IQR) healthcare-associated costs in the year after cardiac arrest were €47,000 (€28,000-75,000) in 1-year survivors and €12,000 (€6600-25,000) in non-survivors. In a multivariate linear regression model adjusting for age and prior independency in self-care, an increase of one point in the 24h-EC-SOFA score was associated with an increase of €170 (95% CI €150-190) in the cost per day alive in the year after cardiac arrest. In the same model, an increase of one point in the 24h-EC-SOFA score was associated with an increase of €4400 (95% CI €3300-5500) in the total healthcare-associated costs in 1-year survivors. CONCLUSIONS: Extracerebral organ dysfunction is associated with long-term outcome and gross healthcare-associated costs of ICU-treated cardiac arrest patients. It should be considered when assessing interventions to improve outcomes and optimize the use of resources in these patients.

Outcomes and healthcare-associated costs one year after intensive care-treated cardiac arrest.

BACKGROUND: Despite the significant socioeconomic burden associated with cardiac arrest (CA), data on CA patients' long-term outcome and healthcare-associated costs are limited. The aim of this study was to determine one-year survival, neurological outcome and healthcare-associated costs for ICU-treated CA patients. METHODS: This is a single-centre retrospective study on adult CA patients treated in Finnish tertiary hospital's ICUs between 2005 and 2013. Patients' personal identification number was used to crosslink data between several nationwide databases in order to obtain data on one-year survival, neurological outcome, and healthcare-associated costs. Healthcare-associated costs were calculated for every patient stratified by cardiac arrest location (OHCA = out-of-hospital cardiac arrest, IHCA = all in-hospital cardiac arrest, ICU-CA = in-ICU cardiac arrest) and initial cardiac rhythm. Cost-effectiveness was estimated by dividing total healthcare-associated costs for all patients from the respective group by the number of survivors and survivors with favourable neurological outcome. RESULTS: The study population included 1,024 ICU-treated CA patients. The sum of costs for all patients was €50,847,540. At one-year after CA, 58% of OHCAs, 44% of IHCAs, and 39% of ICU-CAs were alive. Of one-year survivors 97% of OHCAs, 88% of IHCAs, and 93% of ICU-CAs had favourable neurological outcome. Effective cost per one-year survivor was €76,212 for OHCAs, €144,168 for IHCAs, and €239,468 for ICU-CAs. Effective cost per one-year survivor with favourable neurological outcome was €81,196 for OHCAs, €164,442 for IHCAs, and €257,207 for ICU-CAs. CONCLUSIONS: In-ICU CA patients had the lowest one-year survival with the effective cost per survivor three times higher than for OHCAs.

Successful implementation of an Enhanced Recovery After Surgery program shortens length of stay and improves postoperative pain, and bowel and bladder function after colorectal surgery.

BACKGROUND: Despite international data indicating that Enhanced Recovery After Surgery (ERAS) programs, which combine evidence-based perioperative strategies, expedite recovery after surgery, few centers have successfully adopted this approach within the U.S. We describe the implementation and efficacy of an ERAS program for colorectal abdominal surgery in a tertiary teaching center in the U.S. METHODS: We used a multi-modal and continuously evolving approach to implement an ERAS program among all patients undergoing colorectal abdominal surgery at a single hospital at the University of California, San Francisco. 279 patients who participated in the Enhanced Recovery after Surgery program were compared to 245 previous patients who underwent surgery prior to implementation of the program. Primary end points were length of stay and readmission rates. Secondary end points included postoperative pain scores, opioid consumption, postoperative nausea and vomiting, length of urinary catheterization, and time to first solid meal. RESULTS: ERAS decreased both median total hospital length of stay (6.4 to 4.4 days) and post-procedure length of stay (6.0 to 4.1 days). 30-day all-cause readmission rates decreased from 21 to 9.4 %. Pain scores improved on postoperative day 0 (3.2 to 2.1) and day 1 (3.2 to 2.6) despite decreased opioid. Median time to first solid meal decreased from 4.7 to 2.7 days and duration of urinary catheterization decreased from 74 to 46 h. Similar improvements were observed in all other secondary end points. CONCLUSIONS: These results confirm that a multidisciplinary, iterative, team-based approach is associated with a reduction in hospital stay and an acceleration in recovery without increasing readmission rates.

Intravenous lipid emulsion given to volunteers does not affect symptoms of lidocaine brain toxicity.

Intravenous lipid emulsion has been suggested as treatment for local anaesthetic toxicity, but the exact mechanism of action is still uncertain. Controlled studies on the effect of lipid emulsion on toxic doses of local anaesthetics have not been performed in man. In randomized, subject-blinded and two-phase cross-over fashion, eight healthy volunteers were given a 1.5 ml/kg bolus of 20% Intralipid(®) (200 mg/ml) or Ringer's acetate solution intravenously, followed by a rapid injection of lidocaine 1.0 mg/kg. Then, the same solution as in the bolus was infused at a rate of 0.25 ml/kg/min. for 30 min. Electroencephalography (EEG) was recorded, and 5 min. after lidocaine injection, the volunteers were asked to report subjective symptoms. Total and un-entrapped lidocaine plasma concentrations were measured from venous blood samples. EEG band power changes (delta, alpha and beta) after the lidocaine bolus were similar during lipid and during Ringer infusion. There were no differences between infusions in the subjective symptoms of central nervous system toxicity. Lidocaine was only minimally entrapped in the plasma by lipid emulsion, but the mean un-entrapped lidocaine area under concentration-time curve from 0 to 30 min. was clearly smaller during lipid than Ringer infusion (16.4 versus 21.3 mg × min/l, p = 0.044). Intravenous lipid emulsion did not influence subjective toxicity symptoms nor affect the EEG changes caused by lidocaine.

Intravenous lipid emulsion entraps amitriptyline into plasma and can lower its brain concentration--an experimental intoxication study in pigs.

Intravenous lipid emulsion has been suggested as treatment for severe intoxications caused by lipophilic drugs, including tricyclic antidepressants. We investigated the effect of lipid infusion on plasma and tissue concentrations of amitriptyline and haemodynamic recovery, when lipid was given after amitriptyline distribution into well-perfused organs. Twenty anaesthetized pigs received amitriptyline intravenously 10 mg/kg for 15 min. Thirty minutes later, in random fashion, 20% Intralipid(®) (Lipid group) or Ringer's acetate (Control group) was infused 1.5 ml/kg for 1 min. followed by 0.25 ml/kg/min. for 29 min. Arterial and venous plasma amitriptyline concentrations and haemodynamics were followed till 75 min. after amitriptyline infusion. Then, frontal brain and heart apex samples were taken for amitriptyline measurements. Arterial plasma total amitriptyline concentrations were higher in the Lipid than in the Control group (p < 0.03) from 20 min. on after the start of the treatment infusions. Lipid emulsion reduced brain amitriptyline concentration by 25% (p = 0.038) and amitriptyline concentration ratios brain/arterial plasma (p = 0.016) and heart/arterial plasma (p = 0.011). There were no differences in ECG parameters and no severe cardiac arrhythmias occurred. Two pigs developed severe hypotension during the lipid infusion and were given adrenaline. In conclusion, lipid infusion, given not earlier than after an initial amitriptyline tissue distribution, was able to entrap amitriptyline back into plasma from brain and possibly from other highly perfused, lipid-rich tissues. In spite of the entrapment, there was no difference in haemodynamics between the groups.

In vitro and in vivo entrapment of bupivacaine by lipid dispersions.

Intravenous lipid emulsion is recommended as treatment for local anesthetic intoxication based on the hypothesis that the lipophilic drug is entrapped by the lipid phase created in plasma. We compared a 15.6 mM 80/20 mol% phosphatidyl choline (PC)/phosphatidyl glycerol (PG)-based liposome dispersion with the commercially available Intralipid® emulsion in a pig model of local anesthetic intoxication. Bupivacaine-lipid interactions were studied by electrokinetic capillary chromatography. Multilamellar vesicles were used in the first in vivo experiment series. This series was interrupted when the liposome dispersion was discovered to cause cardiovascular collapse. The toxicity was decreased by an optimized sonication of the 50% diluted liposome dispersion (7.8 mM). Twenty anesthetized pigs were then infused with either sonicated PC/PG liposome dispersion or Intralipid®, following infusion of a toxic dose of bupivacaine which decreased the mean arterial pressure by 50% from baseline. Bupivacaine concentrations were quantified in blood samples using liquid chromatography/mass spectrometry. No significant difference in the context-sensitive plasma half-life of bupivacaine was detected (p=0.932). After 30 min of lipid infusion, the bupivacaine concentration was 8.2±1.5 mg/L in the PC/PG group and 7.8±1.8 mg/L in the Intralipid® group, with no difference between groups (p=0.591). No difference in hemodynamic recovery was detected between groups (p > 0.05).

No antidotal effect of intravenous lipid emulsion in experimental amitriptyline intoxication despite significant entrapment of amitriptyline.

Intravenous lipid emulsion has been used in the resuscitative treatment of intoxications caused by local anaesthetics and tricyclic antidepressants with seemingly beneficial results. We studied the effect of intravenous lipid emulsion on the plasma concentration of amitriptyline and haemodynamic recovery in a pig model of amitriptyline intoxication. Twenty pigs were anaesthetized (1% isoflurane in 21% O(2)) and given amitriptyline 15 mg/kg intravenously for 15 min. In random fashion immediately thereafter, either 20% lipid emulsion (ClinOleic(®), Lipid group) or Ringer's acetate (Control group) was infused for 30 min.; first 1.5 ml/kg for 1 min., followed by 0.25 ml/kg/min. for 29 min. The amitriptyline concentration in total and lipid-poor plasma and haemodynamic parameters were measured until 30 min. after the infusions. Lipid infusion prevented the decrease in plasma total amitriptyline concentration, resulting in a 90% higher (p < 0.001) total concentration and significantly (p = 0.014) lower free fraction of plasma amitriptyline in the Lipid group (1.1%) compared with the Control group (3.0%) at 30 min. Haemodynamic recovery from the intoxication as measured by heart rate, arterial pressure or cardiac output was similar in both groups. However, five pigs in the Lipid group and two pigs in the Control group died. In conclusion, a marked entrapment of amitriptyline by intravenous lipid emulsion was observed but this did not improve the pigs' haemodynamic recovery from severe amitriptyline intoxication. Care should be exercised in the antidotal use of lipid emulsion until controlled human studies indicate its efficacy and safety.

Intravenous lipid emulsion only minimally influences bupivacaine and mepivacaine distribution in plasma and does not enhance recovery from intoxication in pigs.

BACKGROUND: The reported successful use of IV lipid emulsions in local anesthetic intoxications is thought to be due to lipid sequestration of local anesthetics. However, controlled efficacy studies were lacking, and other mechanisms of action have also been suggested. We investigated the effect of lipid infusion on plasma concentrations and cardiovascular effects of 2 local anesthetics differing in lipophilicity, bupivacaine, and mepivacaine. METHODS: Bupivacaine (n = 20) or mepivacaine (n = 20) was infused into a central vein of anesthetized (isoflurane 1%, Fio(2) 0.21) pigs until mean arterial blood pressure decreased to 50% from baseline. Isoflurane was discontinued and Fio(2) was increased to 1.0. Ten pigs in each local anesthetic group were treated with 20% lipid emulsion (ClinOleic®), and 10 pigs with Ringer's solution: 1.5 mL/kg in 1 minute followed by an infusion of 0.25 mL · kg(-1) · min(-1) for 29 minutes. Five additional pigs were infused bupivacaine and Intralipid®. Total and nonlipid-bound local anesthetic concentrations were determined from repeated blood samples. RESULTS: There were no overall differences in total or nonlipid-bound plasma local anesthetic concentrations between the lipid and Ringer's groups. However, plasma median total bupivacaine concentration was 21% and 23% higher at 20 and 30 minutes, respectively, in the lipid group (P = 0.016 without Holm-Bonferroni correction). There was also no overall difference between lipid and Ringer's groups in the rate of recovery of hemodynamic and electrocardiographic variables. Median mean arterial blood pressure in the lipid group with bupivacaine intoxication was 16 mm Hg and 15 mm Hg higher than in the corresponding Ringer's group at 10 and 15 minutes, respectively (P = 0.016 and P = 0.021, respectively, without Holm-Bonferroni correction). Intralipid® also caused no difference between total plasma and nonlipid-bound concentrations of bupivacaine with no apparent enhancement of recovery. CONCLUSIONS: Lipid emulsion neither had any measurable effect on the disposition of the studied local anesthetics in plasma, nor did it improve the rate of recovery from intoxication by either local anesthetic as measured by hemodynamic variables.