

### Intralipid Is a Magic Bullet

Published by

### JOSEPH ELDOR

Contributors

TUAN ANH NGUYEN

KIEN TRUNG NGUYEN

THUY QUANG LUU

KIEN TRUNG NGUYEN

PHAT NGOC HO

VY NGUYEN

SON TRUONG DO

HUY THANH DO

VO VAN HIEN

DAO THI KHANH

VI PHAM

TAM PHUOC TRAN

XUAN LOC NGUYEN

DUNG VAN PHAN

THANH THE DANG

Copyright ©2018 by Joseph Eldor

Smashwords Edition

All rights reserved. No part of this book may be used or reproduced in any manner whatsoever without written permission, except in the case of brief quotations embodied in critical articles or reviews. Please do not participate in or encourage the piracy of copyrighted materials in violation of the author's rights. Purchase only authorized editions.

### THE AUTHORS

1. JOSEPH ELDOR : Theoretical Medicine Institute, Jerusalem, Israel

2. TUAN ANH NGUYEN : Department of Anesthesiology and Pain Medicine, University Medical Center, Hochiminh City, Vietnam

3. KIEN TRUNG NGUYEN : Department of Anesthesiology and Pain Medicine, Millitary University Hospital 103, Military University of Medicine, Vietnam

4. THUY QUANG LUU : Center of Anesthesiology and Surgical Intensive Care, Vietnam - Germany University Hospital, Ha Noi, Viet Nam

5. KIEN TRUNG NGUYEN : Surgical ICU, Nghe An General Friendship Hospital, Nghe An Province, Viet Nam

6. PHAT NGOC HO : Department of Anesthesiology and ICU, 175 Military Hospital, Ho Chi Minh City, Viet Nam

7. VY NGUYEN : Department of Anesthesiology, My Duc Obstetric and Gynecology Hospital, Ho Chi Minh City, Viet Nam

8. SON TRUONG DO : Faculty of Surgery, Hanoi University of Medicine, Head of Department of Surgery, E Hospital, Ha Noi, Viet Nam

9. HUY THANH DO : Pain Clinic, Hoan My Cuu Long Hospital, Can Tho, Vietnam

10. VO VAN HIEN : Department of Anesthesia and Pain Medicine, Military Hospital 103, Vietnam Military Medical University

11. DAO THI KHANH : Department of Pharmacy, Military Hospital 103, Vietnam Military Medical University

12. VI PHAM : La Gi Region General Hospital, Binh Thuan, Vietnam

13. TAM PHUOC TRAN : Thanh Tam Private Hospital, Binh Phuoc Province, Vietnam

14. XUAN LOC NGUYEN : Hai Duong Obstetric and Gynecological Hospital, Hai Duong Province, Vietnam

15. DUNG VAN PHAN : Department of Anesthesiology and Pain Medicine, University Medical Center, Hochiminh City, Vietnam

16. THANH THE DANG : Department of Anesthesiology, Daklak General Hospital, Vietnam

### Contents

1. Lipid Emulsion Treatment (LET) of Post Operative Cognitive Dysfunction (POCD)

2. Local Anesthesia Reversal (LAR) of Spinal Anesthesia by Lipid Emulsion (Lipofundin 20%) for Day Case Surgery

3. Upper Arm Local Anesthesia Reversal (LAR) Using Lipofundin (3 Case Reports)

4. Local Anesthesia Reversal (LAR) of Total Spinal Anesthesia (TSA) by Lipofundin (Lipid Emulsion)

5. The First Case Report of Local Anesthesia Reversal (LAR) of the Upper Arm Brachial Plexus Block by Lipid Emulsion

6. Lipid Emulsion for Local Anesthesia Reversal (LAR) after Prolonged Spinal/Epidural Anesthesia

7. Lipid Emulsion Treatment for Post Spinal Anesthesia Myoclonus

### Based on 7 articles from the Journal of Health Science and Development

1. Lipid Emulsion Treatment (LET) of Post Operative Cognitive Dysfunction (POCD)

<http://innovationinfo.org/articles/JHSD-112.pdf>

2. Local Anesthesia Reversal (LAR) of Spinal Anesthesia by Lipid Emulsion (Lipofundin 20%) for Day Case Surgery

<http://innovationinfo.org/articles/JHSD-111.pdf>

3. Upper Arm Local Anesthesia Reversal (LAR) Using Lipofundin (3 Case Reports)

<http://innovationinfo.org/articles/JHSD-110.pdf>

4. Local Anesthesia Reversal (LAR) of Total Spinal Anesthesia (TSA) by Lipofundin (Lipid Emulsion)

<http://innovationinfo.org/articles/JHSD-109.pdf>

5.The First Case Report of Local Anesthesia Reversal (LAR) of the Upper Arm Brachial Plexus Block by Lipid Emulsion

<http://innovationinfo.org/articles/JHSD-108.pdf>

6. Lipid Emulsion for Local Anesthesia Reversal (LAR) after Prolonged Spinal/Epidural Anesthesia

<http://innovationinfo.org/articles/JHSD-106.pdf>

7. Lipid Emulsion Treatment for Post Spinal Anesthesia Myoclonus

<http://innovationinfo.org/articles/JHSD-104.pdf>

Lipid Emulsion Treatment (LET) of Post-Operative Cognitive Dysfunction (POCD)

List of Author(s): Tuan Anh Nguyen, Kien Trung Nguyen, Thuy Quang Luu, Kien Trung Nguyen, Phat Ngoc Ho, Vy Nguyen, Son Truong Do, Huy Thanh Do, Joseph Eldor.

Abstract

Postoperative delirium (POD) or Post-operative cognitive dysfunction (POCD) is a common and serious adverse event in the elderly patient and is associated with significant morbidity and mortality. A new treatment for POD/POCD by intravenous Intralipid (lipid emulsion) injection in the recovery room was first suggested by Eldor on 2017  (http:// medcraveonline.com/JACCOA/JACCOA-07-00273.pdf). The 4 case reports in this article describing the successful use of lipid emulsions (Smoflipid 20% and Lipidem 20%) are the first case reports of Lipid Emulsion Treatment (LET) of Post-operative cognitive dysfunction (POCD) in the medical literature.

Keywords

Post-operative Cognitive Dysfunction, POCD, Postoperative Delirium, POD, Lipid Emulsion, Intralipid, Smoflipid, Lipidem, Mitochondria.

NOTICE: All the 4 patients mentioned in this article have given their signed written permission to use their video clips taken in the recovery room for scientific purposes to all the scientific community all over the world.

Case Reports

Case 1

82 years old male, hospitalized because of abscess of the muscle on the back (thoracic part). He has type 2 diabetes, common pulmonary infection. The first surgery for abscess drainage was under local anesthesia uneventfully. He was under antibiotic (Vancomycin 1gr, Cefriaxon 1gr), Acetaminophen 1gr, Voltaren (NSAIDS) 50mg IM/day, Omeprazol 40 mg/day for 7 days.

He had been under second surgery for larger incision to drain the abscess under balanced general anesthesia with ETT, Propofol 200 mg, Fentanyl 150mcg, Rocuronium 35 mg. Bridion 200 mg (Sugammadex) was used to reverse the residual muscle relaxant before extubation. The surgery time was 40 min.

After extubation, patient had been agitated, uncooperative, incomprehensible communication. Because he risked to falling and taking the IV line by his own, textile strings were used to tide his arms to bed. He was given 1 vial of Haloperidol IM, 2.5 mg IV bolus of midazolam, but the situation had not improved after 60 min.

We decided to start Lipid Emulsion Therapy (LET): 250ml IV Smoflipid 20% (Fresenius Kabi) over 30 min, and continued the second vial over 120 min thereafter. The effectiveness of LET: At 30 min after finishing the first 250ml Smoflipid 20%, patient was calmer, could talk with comprehensible phrases. Because he could not speak Vietnamese, so we asked his relative to communicate with him. He was cooperative, but he was a little bit relentless. The strings were released regarding his demand and lesser risk of unattended behaviours estimated by staffs. The second vial of 250 ml Smoflipid 20 % had been continued.

1. At 60 min, he was cooperative, comprehensible communication, no agitation. The strings were taken out when risk of inappropriate behaviours were lessen.

2. At 180 min (3 h), he was calm, cooperative, thirsty, hungry. We let him sitting up with the care of his relative.

3. At 240 min, Termination of the second vial of LET, he was nearly normal and had been returned to ward.

Video Clip Case 1:  https://youtu.be/eNclUfCqntc

Case 2

77 years old Male admitted to hospital due to acute gangrenous cholecystitis. His past medical history was type 2 diabetes, hypertension, coronary ischemic disease, cerebral ischemic attack for 10 years ago, Parkinson. Cerebral CT Scan revealed the occupational region on the left orbit. Thoracic CT Scan also revealed a thoracic aortic aneurysm. FBC; WBC: 19.36 G/l, NEU 92.8%, Glusose: 8.2 mmol/L, Total Bilirubin: 71.72 mmol/L, Direct Bilirubin: 32.4 mmol/L, ASAT: 352 U/L, ALAST: 265 U/L, Na+: 135 mmol/L, K: 4.2 mmol/L, Calcium: 102 mmol/L, CPR: 35.2 mg/L, CK-MB: 20 U/L, Creatinine: 1.36 mg/dL, Urea: 40.15 mg/dL, ECG: ischemic heart disease on the anterior wall. BP: 180/90 mm Hg, HR 90 BPM, BR 16, Temperature 38.5. He was fully conscious, cooperative, no localized neurologic signs, no chest pain.

He was treated by antibiotic (Meropenem 1gr IV). Because his condition was so frail so the radical surgery was not planned. The Percutaneous Transhepatic Biliary Drainage (PTBD) was proposed to relief the symptoms. He was under local anesthesia with sedative (Propofol 50mg+Fentanyl 100 mcg) with Oxygen cannula. The PTBD procedure was 30 min under the ultrasound and Fluoroscopy.

In the recovery room, his mental status was disoriented, agitated, incomprehensible communication, relentless. He was tied to the bed by strings because of falling risk.

1. We started LET by IV infusion 250 ml Lipidem 20%, (B.Braun) over 30 min. After 100 ml Lipidem 20% infused over 10 min, patient was less relentless, calmer, less agitated, communication became easier. The second vial 250 ml of Lipidem 20 % was continued in 30 min.

2. Approximately 120 min after LET, patient was not agitated, cooperative, comprehensible communication, the strings were released.

3. 4 h after LET, his mental status was nearly normal as before having surgery. He was returned to the ward. He was uneventful thereafter.

Video Clip Case 2:  https://youtu.be/1Wqz4wNkhPo

Case 3

81 years old male, benign prostate enlargement hospitalized for Trans Urethral Resection of Prostate (TURP). His past medical story was hypertension, ischemic heart disease. He had closed head trauma 5 years ago, but no mental disorientation thereafter. He was cooperative, nondependent activity in daily life.

The laboratory pre-operative tests were non-specific. Ionogram: Na 140 mmol/dL, K 3.4 mmol/dL, Cl 107 mmol/ dL, Urea 52.73 mmol/dL, Creatinine 1.1 mmol/dL, Glucose 8.8 mmol/dL. ECG revealed the chronic ischemic heart disease, but the conserved heart function (Left Ventricular EF: 72%).

He was under Spinal Anesthesia for TURP. The BP before SA 180/100, HR 85 BPM, SpO2 99 %, Midazolam 2 mg IV for sedation before SA puncture at L3-4, dose was 8 mg Heavy Bupivacaine 0.5%+20 mcg Fentanyl. The surgery time was 20 min, the irrigation solution was 1000 ml per operation, the crystalloid solution given per operation was 500 ml NaCl 0.9%, no vasoconstrictor used.

For post-operative:

1. Tramadol 100 mg IV diluted in 100 ml NaCl 0.9%, interval 8 hrs

2. Odansetron 8 mg IV

3. Omeprazol 40mg IV

4. NaCl 0.9% 1000 ml for irrigation.

3 hrs post operation, his mental status was very disorientated, agitated, yelling, screaming. The on duty anesthesiologist had used 2.5 mg Midazolam bolus + Propofol infusion to sedate him. As soon as infusion finished, the mental crisis rebound and 5 mg I.M Haloperidol was given during the night, but was not effective as the Propofol infusion.

On the next morning, his crisis rebound severely, so several nurses had to tie him to the bed.

1. We diagnosed this acute mental crisis as Postoperative Delirium. There were two possibilities that may cause POD on this patient: the TURP Syndrome and The Serotonin Syndrome (due to Tramadol).

2. We decided to use LET as challenging therapy. First vial of 250 ml Lipidem 20 % intravenously was given over 60 min.

3. After 30 min after LET, he was calm, less agitated, comprehensible communication.

4. 60 min after LET, he was calm, cooperative, comprehensible communication, he was thirsty and asked for drink.

5. 120 min after LET, the mental crisis was nearly gone, he was released from the strings, he drank and eat soft foods. The ionogram revealed the Na 131 mmol/dL, K 3.03 mmol/dL, Cl 99 mmol/dL.

6. 240 min (4h) after LET, he was a little bit more relentless, but cooperative, comprehensible communication. He complained of discomfort due to urine catheter. We decided to use the second vial of 250 ml Lipidem 20% to maintain the effectiveness.

7. 8 h from the LET, patient was calm, oriented, well communicated, comfortable, not complained on urine catheter, he drank, eaten normally.

8. No mental crisis thereafter.

Video clip case 3 :  https://youtu.be/ZKOaOqdEPL0

Case 4

79 years old hypertensive female, hospitalized in emergency for biliary duct infection. Her vital signs were stable, temperature 38.5, BP 130/80, HR 80 BPM. The CT scan revealed the intra and extra hepatic biliary duct dilatation with the stone at the end of common bile duct. FBC: WBC 16 G/l, Neu 88.9%, Total Billirubin 117.2 mmol/L, direct Billirubin 70 mmol/l, AST 89UI/l, ALT 54 UI/L, Glucose 86 mg/dL, Urea 37 mg/dL, K 2.93 mmol/L, Cl 102 mmol/L, Troponin 0.024 ng/ml.

She was treated by antibiotic (Meropenem 1000mg every 8h + Metronidazole 500mg every 8 h) and was indicated for ERCP procedure. (Endoscopic Retrograde Cholangio - Pancreatography).

She was under general anesthesia with ETT. The balanced anesthesia with Propofol, Fentanyl, Rocuronium, Servoran was uneventfull, she was neutralized by Bridion 100 mg (Sugammadex) before extubation. The surgery lasted for 40 mins.

At recovery room, she was relentless, slight agitated, but not disorientated, comprehensible communication, but complained of discomfort at abdomen, not pain. The vital signs were stable. Because she was overweight and risk of falling, taking out the IV line by her own, so the strings were used to tie her arms to the bed.

We decided to use LET for this situation.

1. 250 ml Lipidem 20% was intravenously infused over 60 min.

2. After 30 min LET, her mental status seemed better, but not clear, the strings were released for her comfort

3. After 60 min LET, her mental status was improved significantly. She was less relentless, less agitated, cooperative, better communication. She asked for drink.

4. After 120 min, she was with better communication, cooperative, smiled, "did not remember what had happened before".

5. At 180 min, the mental status was nearly the same. We decided to continue the second vial 250 of Lipidem 20% for sustainable effectiveness.

Video Clip of Case 4 :  https://youtu.be/w38n8tdtQ6Y

Discussion

Post-Operative Delirium/ Post-Operative Cognitive Dysfunction

Delirium is defined by either the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) [1] or by the 10th revision of the International Statistical Classification of Diseases and Related Health Problems (ICD 10, Table 3) [2]. Delirium is an acute and fluctuating alteration of mental state of reduced awareness and disturbance of attention. POD (Post-Operative Delirium) often starts in the recovery room and occurs up to 5 days after surgery [3-5]. One investigation [4] found that many patients with POD on the peripheral ward already had POD in the recovery room.

More than 230 million surgical procedures are performed each year worldwide, of which more than 80 million are in Europe [6-8]. In Europe, the in-hospital mortality rates up to a maximum of 60 days is 3% after elective surgery and nearly 10% after emergency surgery [7]. In addition to mortality, postoperative cognitive impairments such as POD and postoperative cognitive dysfunction (POCD) impose a huge burden on individuals and society [9]. The incidence of POD is dependent on perioperative and intraoperative risk factors [10]. Therefore, the incidence of POD varies within a broad range [11,12]. For example, a meta-analysis of 26 studies of POD reported an incidence of 4.0 to 53.3% in hip fracture patients and 3.6 to 28.3% in elective patients [13].

Delirium is one of the most common complications following hip fracture surgery in older people. This study identified pre- and peri-operative factors associated with the development of post-operative delirium following hip fracture surgery.

Published and unpublished literature were searched to identify all evidence reporting variables on patient characteristics, on-admission, intra-operative and postoperative management assessing incident delirium in older people following hip fracture surgery. Pooled odds ratio (OR) and mean difference of those who experienced delirium compared to those who did not were calculated for each variable. Evidence was assessed using the Downs and Black appraisal tool and interpreted using the GRADE approach.

A total of 6704 people (2090 people with post-operative delirium) from 32 studies were analysed. There was moderate evidence of nearly a two-times greater probability of post-operative delirium for those aged 80 years and over (OR: 1.77; 95% CI: 1.09, 2.87), whether patients lived in a care institution pre-admission (OR: 2.65; 95% CI: 1.79, 3.92), and a six-times greater probability of developing post-operative delirium with a pre-admission diagnosis of dementia (OR: 6.07, 95% CI: 4.84, 7.62). There was no association with intra-operative variables and probability of delirium.

Clinicians treating people with a hip fracture should be vigilant towards post-operative delirium if their patients are older, have pre-existing cognitive impairment and poorer overall general health. This is also the case for those who experience post-operative complications such as pneumonia or a urinary tract infection [14].

Post-operative cerebral dysfunction includes delirium, usually occurring early and reversible, and post-operative cognitive disorders, usually occurring later and prolonged. This is a frequent complication in patients older than 75 years old. The two neurological pictures are often interrelated. The pathophysiology of both entities is similar and related to post-operative neuro-inflammation; therefore, onset may occur independently of any surgical complication. Post-operative cerebral dysfunction is a serious organic complication. Reduction of inflammation represents the most logical preventive measure but currently there are no studies that show this to be effective. Prevention therefore means combining several minor measures, elements that fit well into programs of enhanced post-operative recovery after surgery. Diminished pre-operative cognitive status being a major risk factor, pre-operative rehabilitation combining nutritional, physical and cognitive support can be helpful [15].

Postoperative delirium is a common and serious adverse event in the elderly patient and is associated with significant morbidity and mortality. It is of great importance to identify patients at risk for delirium, in order to focus preventive strategies. The aim of this article is to systematically review current available literature on pre-operative risk factors for delirium after vascular surgery.

A systematic literature search was conducted using PubMed and EMBASE, using the MeSH terms and key words "delirium", "surgery" and "risk factor". Studies were retained for review after meeting strict inclusion criteria that included only prospective studies evaluating risk factors for delirium in patients who had elective vascular surgery. Diagnosis of delirium needed to be confirmed using the Diagnostic and Statistical Manual of Mental Disorders (DSM) or ICD-10.

Fifteen articles were selected for inclusion, incidence of delirium across the studies ranged from 5% to 39%. Many factors have been associated with increased risk of delirium, including age, cognitive impairment, comorbidity, depression, smoking, alcohol, visual and hearing impairment, ASA-score, biochemical abnormalities, operative strategies and blood loss.

Delirium is a common complication after elective vascular surgery in elderly. The highest delirium incidence was observed after open aortic surgery as well as after surgery for critical limb ischemia. A picture starts to form of which predisposing factors lead to increased risk of delirium. The leading risk factors consistently identified in this systematic review were advanced age and cognitive impairment. Multidisciplinary specialist-led interventions in the preoperative phase could decrease incidence and severity of delirium and should be focused on identified high-risk patients [16].

This study [17] investigates the relationship between cognitive dysfunction or delirium detected in the early post-surgical phase and the 1-year mortality among 514 hip fracture hospitalized older persons. Patients with early cognitive dysfunction or delirium experienced a 2-fold increased mortality risk. Early post-operative cognitive dysfunction and delirium are negative prognostic factors for mortality.

Premorbid cognitive impairment and dementia in older individuals negatively affect functional recovery after hip fracture. Additionally, post-operative delirium is an established risk factor for negative outcomes among hip fracture patients. While the majority of hip fracture patients experience minor post-surgical cognitive dysfunction, the prognostic value of this phenomenon is unknown. Therefore, we investigated the relationship between minor cognitive dysfunction or delirium detected in the early post-surgical phase and the 1-year mortality after index hip fracture.

We enrolled 514 patients with hip fracture (77.4% women), aged 65 years or older (mean age 83.1 ± 7.3 years), who underwent surgical hip fracture repair. Patients were assessed daily from the second to the fourth post-operative day and at 3, 6, and 12 months thereafter. All participants underwent comprehensive assessment, including detection of delirium by using the confusion assessment method and evaluation of cognitive function by using mini-mental state examination (MMSE; score range 0 to 30, with lower scores indicating poorer performance). In the absence of delirium, post-surgical cognitive dysfunction was defined as having low performance on MMSE. Vital status of 1 year after the index fracture and date of death were gathered from local registries.

The observed 1-year mortality rate was 14.8%. Men were more likely to die than women within 1 year of the index fracture (p<0.01). Compared to participants with better cognitive performance, those with MMSE <24, as well as those with delirium in the post-operative phase, showed a significantly higher 1-year mortality rate (23.3 versus 17.9 and 8.1%, respectively). Independent of age and sex, postoperative cognitive dysfunction as well as delirium was both associated with a 2-fold increased mortality risk.

The presence of minor cognitive dysfunction in the early post-surgical phase is a negative prognostic factor for mortality among elderly hip fracture patients. The burden of minor cognitive dysfunction is likely superimposed on that of delirium in subgroups of frail patients [17].

Perioperative cerebral hypo-perfusion/ischemia is a major inciting factor of postoperative delirium, which is coupled with adverse outcome in elderly patients. Cerebral oximetry enables non-invasive assessment of the regional cerebral oxygen saturation (rSO2). This study aimed to investigate whether perioperative rSO2variations were linked to delirium in elderly patients after spinal surgery.

Postoperative delirium was assessed for 48 hrs postsurgery in 109 patients aged over 60 years without a prior history of cerebrovascular or psychiatric diseases by the Confusion Assessment Method for the intensive care unit and the intensive care delirium screening checklist. The rSO2 values immediately before and throughout surgery were acquired. The preoperative cognitive functions, patient characteristics, and perioperative data were recorded.

During the 48-h postoperative period, 9 patients (8%) exhibited delirium. The patients with delirium showed similar perioperative rSO2 values as those without, in terms of the median lowest rSO2 values (55% vs. 56%; P=0.876) and incidence (22%, both) and duration of decline of rSO2<80% of the baseline values. The serially assessed hemodynamic variables, haematocrit levels, and blood gas analysis variables were also similar between the groups, except for the number of hypotensive events per patient, which was higher in the patients with delirium than in those without (4, interquartile range [IQR] 3 to 6 vs. 2, IQR: 1to 3; P=0.014).

The degree and duration of decrease of the perioperative rSO2 measurements were not associated with delirium in elderly patients after spinal surgery [18].

Three-dimensional Arterial Spin Labeling (ASL) MRI was performed before surgery in a cohort of 146 prospectively enrolled subjects ≥ 70 years old scheduled to undergo elective surgery. We investigated the prospective association between ASL-derived measures of cerebral blood flow (CBF) before surgery with postoperative delirium incidence and severity using whole-brain and globally normalized voxel-wise analysis. We also investigated the cross-sectional association of CBF with patients' baseline performance on specific neuropsychological tests, and with a composite general cognitive performance measure (GCP). Out of 146 subjects, 32 (22%) developed delirium. We found no significant association between global and voxelwise CBF with delirium incidence or severity. We found the most significant positive associations between CBF of the posterior cingulate and precuneus and the Hopkins Verbal Learning Test-Revised total score, Visual Search and Attention Test (VSAT) score and the GCP composite. VSAT score was also strongly associated with right parietal lobe CBF. ASL can be employed in a large, well-characterized older cohort to examine associations between CBF and agerelated cognitive performance. Although ASL CBF measures in regions previously associated with preclinical Alzheimer's Disease were correlated with cognition, they were not found to be indicators of baseline pathology that may increase risk for delirium [19].

Oxidative stress may be involved in occurrence of postoperative delirium (POD) and cognitive dysfunction (POCD). 8-iso-Prostaglandin F2 α (8-iso-PGF2 α ), an isoprostane derived from arachidonic acid via lipid peroxidation, is considered a gold standard for measuring oxidative stress. The present study aimed to investigate the ability of postoperative plasma 8-iso-PGF2 α levels to predict POD and POCD in elderly patients undergoing hip fracture surgery.

Postoperative plasma 8-iso-PGF2 α levels of 182 patients were measured by an enzyme-linked immunosorbent assay. We assessed the relationships between plasma 8-iso-PGF2 α levels and the risk of POD and POCD using a multivariate analysis.

Plasma 8-iso-PGF2 α levels and age were identified as the independent predictors for POD and POCD. Based on areas under receiver operating characteristic curve, the predictive values of 8-iso-PGF2 α were obviously higher than those of age for POD and POCD. In a combined logistic-regression model, 8-iso-PGF2 α significantly enhanced the areas under curve of age for prediction of POD and POCD.

Postoperative plasma 8-iso-PGF2 α levels may have the potential to predict POD and POCD in elder patients undergoing hip fracture surgery [20].

Risk factors for delirium following cardiac surgery are incompletely understood. The aim of this study was to investigate whether intra-operative pathophysiological alterations and therapeutic interventions influence the risk of post-operative delirium.

This retrospective cohort study was performed in a 12- bed cardio-surgical intensive care unit (ICU) of a university hospital and included patients consecutively admitted after cardiac surgery during a 2-month period. The diagnosis of delirium was made clinically using validated scores. Comparisons between patients with and without delirium were performed with non-parametric tests. Logistic regression was applied to identify independent risk factors. Results are given as number (percent) or median (range).

Of the 194 consecutive post-cardiac surgery patients, 50 (26%) developed delirium during their ICU stay. Univariate analysis revealed that significant differences between patients with and without delirium occurred in the following intra-operative variables: duration of cardiopulmonary bypass (184 [72-299] vs 113 (37-717) minutes, p<0.001), lowest mean arterial pressure (50 [30-70] vs 55 [30-75] mmHg, p = 0.004), lowest haemoglobin level (85 [56-133] vs 98 [53-150] g/L, p = 0.005), lowest body temperature (34.5 [24.4-37.2] vs 35.1 [23.9-37.2] °C, p = 0.035), highest noradrenaline support (0.11 [0.00-0.69] vs 0.07 [0.00-0.42] μ g/kg/minute, p=0.001), and frequency of red blood cell transfusions (18 [36%] vs 26 [18%], p=0.018) and platelet transfusions (23 [46%] vs 24 [17%], p<0.001). Only platelet transfusions remained an independent risk factor in the multivariate analysis (p<0.001).

In patients undergoing cardiac surgery, various intraoperative events, such as transfusion of platelets, were risk factors for the development of a post-operative delirium in the ICU. Further research is needed to unravel the underlying mechanisms [21].

In this study, Bilge EÜ et al. [22] aimed to determine the risk factors and the incidence of delirium in patients who were followed postoperatively in our surgical intensive care unit for 24 hrs using the confusion assessment method (CAM).

After obtaining approval from the ethics committee, 250 patients were included in the study. Patients who were operated under general anaesthesia or regional anaesthesia and followed in the surgical intensive care unit were evaluated by the Ramsay Sedation Scale on the first postoperative day. CAM was applied to the patients who had a Ramsay Sedation Score of ≤ 4. Patients' age, gender, American Society of Anaesthesiologists (ASA) scores, preoperative risk factors, type of anaesthesia, operation time, intra-operative procedures, pain scores evaluated by the visual analogue scale (VAS) and postoperative analgesia methods were recorded.

The incidence of delirium was found to be 18.4%. The average age of patients who developed delirium was greater than the others (68.8 ± 12.7 and 57.6 ± 12, p=0.001, respectively). It was observed that a one-unit increase in the ASA score resulted in a 3.3-fold increase in the risk of delirium. The incidence of delirium in patients undergoing regional anaesthesia was 34.6%, whereas it was 16.5% in patients receiving general anaesthesia (p=0.024). The existence of preoperative diabetes mellitus (DM) and chronic obstructive pulmonary disease (COPD) was shown to improve the development of delirium (p<0.05). Delirium incidence was significantly higher in patients who were administered meperidine for postoperative analgesia (p=0.013). The VAS scores of patients who developed delirium were found to be significantly higher (p=0.006).

As a result, we found that older age, high ASA score, preoperative DM and COPD are important risk factors for the development of delirium. Regional anaesthesia, high postoperative pain scores and meperidine use were observed to be associated with the development of delirium. In the postoperative period, addition of CAM, a simple measurement technique, to the daily follow-up forms can provide the early recognition of delirium, which is often underdiagnosed. We think that identification and prevention of effective risk factors have the primary importance for postoperative delirium [22]./p>

Delirium after cardiac surgery is a major problem. The exact mechanisms behind delirium are not understood. Potential pathways of delirium include neurotransmitter interference, global cognitive disorder, and neuroinflammation. Several predisposing and precipitating risk factors have been identified for postoperative delirium. The development of delirium following cardiac surgery is associated with worse outcomes in the perioperative period. Multiple interventions are being explored for the prevention and treatment of delirium. Studies investigating the potential roles of biomarkers in delirium as well as pharmacological interventions to reduce the incidence and duration of delirium are necessary to mitigate this negative outcome [23].

Perhaps the most frequently described mechanism of brain injury in CABG surgery is based on the recognition that micro-emboli are generated by the surgeon manipulating the heart and aorta, through cardiotomy suctioning, and by the cardiopulmonary bypass circuit itself. Micro-emboli can be detected intraoperatively as high-intensity transient signals by transcranial Doppler sonography. They have the potential to lodge in cerebral microvasculature, impairing blood supply to the brain and thus cerebral oxygenation. Several phases during cardiac surgery have been associated with increased risk of embolic showers. Aortic cannulation and clamping (during application of cardiopulmonary bypass) increase the high-intensity transient signal rate, particularly if there is extensive atheroma in the ascending aorta [24]. It is not surprising, therefore, that most (81%) micro-emboli are generated at the point of aortic cross-clamp release [25]. Retaining the shed mediastinal blood with cardiotomy suckers provides an additional source of lipid emboli and other fragments [26].

Lipid Emulsion-Mitochondrial Sink Effect

Papadopoulou A et al. [27] hypothesized that by substituting a dye surrogate in place of local anesthetic, they could visually demonstrate dye sequestration by lipid emulsion that would be dependent on both dye lipophilicity and the amount of lipid emulsion used.

They selected 2 lipophilic dyes, acid blue 25 and Victoria blue, with log P values comparable to lidocaine and bupivacaine, respectively. Each dye solution was mixed with combinations of lipid emulsion and water to emulate "lipid rescue" treatment at dye concentrations equivalent to fatal, cardio toxic, and neurotoxic local anesthetic plasma concentrations. The lipid emulsion volumes added to each dye solution emulated equivalent intravenous doses of 100, 500, and 900 mL of 20% Intralipid in a 75 kgs adult. After mixing, the samples were separated into a lipidrich supernatant and a lipid-poor subnatant by heparin flocculation. The subnatants were isolated, and their colours compared against a graduated dye concentration scale.

Lipid emulsion addition resulted in significant dye acquisition by the lipid compartment accompanied by a reduction in the colour intensity of the aqueous phase that could be readily observed. The greatest amount of sequestration occurred with the dye possessing the higher log P value and the greatest amount of lipid emulsion.

This study provides a visual demonstration of the lipid sink effect. It supports the theory that lipid emulsion may reduce the amount of free drug present in plasma from concentrations associated with an invariably fatal outcome to those that are potentially survivable.

Local anesthetic (LA) intoxication with cardiovascular arrest is a potential fatal complication of regional anesthesia. Lipid resuscitation has been recommended for the treatment of LA-induced cardiac arrest. Aim of the study [28] was to compare four different rescue regimens using epinephrine and/or lipid emulsion and vasopressin to treat cardiac arrest caused by bupivacaine intoxication.

Twenty-eight piglets were randomized into four groups (4×7), anesthetized with sevoflurane, intubated, and ventilated. Bupivacaine was infused with a syringe driver via central venous catheter at a rate of 1 mg·kg−1·min−1 until circulatory arrest. Bupivacaine infusion and sevoflurane were then stopped, chest compression was started, and the pigs were ventilated with 100% oxygen. After 1 min, epinephrine 10 μ g·kg−1 (group 1), Intralipid (®) 20% 4 ml·kg−1 (group 2), epinephrine 10 μ g·kg−1 + Intralipid (®) 4 ml·kg−1 (group 3) or 2 IU vasopressin + Intralipid (®) 4 ml·kg−1 (group 4) were administered. Secondary epinephrine doses were given after 5 min if required.

Survival was 71%, 29%, 86%, and 57% in groups 1, 2, 3, and 4. Return of spontaneous circulation was regained only by initial administration of epinephrine alone or in combination with Intralipid (®). Piglets receiving the combination therapy survived without further epinephrine support. In contrast, in groups 2 and 4, return of spontaneous circulation was only achieved after secondary epinephrine rescue.

In cardiac arrest caused by bupivacaine intoxication, firstline rescue with epinephrine and epinephrine+Intralipid (®) was more effective with regard to survival than Intralipid (®) alone and vasopressin+Intralipid (®) in this pig model [29].

Local anesthetic (LA) intoxication with severe hemodynamic compromise is a potential catastrophic event. Lipid resuscitation has been recommended for the treatment of LA-induced cardiac arrest. However, there are no data about effectiveness of Intralipid for the treatment of severe cardiovascular compromise prior to cardiac arrest. Aim of this study was to compare effectiveness of epinephrine and Intralipid for the treatment of severe Hemodynamic compromise owing to bupivacaine intoxication, anesthetized Piglets were with sevoflurane, intubated, and ventilated. Bupivacaine was infused with a syringe driver via a central venous catheter at a rate of 1 mg·kg−1·min−1 until invasively measured mean arterial pressure (MAP) dropped to 50% of the initial value. Bupivacaine infusion was then stopped, and epinephrine 3 μ g·kg−1 (group 1), Intralipid (®) 20% 2 ml·kg−1 (group 2), or Intralipid 20% 4 ml·kg−1 (group 3) was immediately administered. Twenty-one piglets (3×7), were recorded. All animals in group 1 (100%) but only four of seven (57%) piglets in group 2 and group 3, respectively, survived. Normalization of hemodynamic parameters (HR, MAP) and ET (CO2) was fastest in group 1 with all piglets achieving HR and MAP values. hemodynamic compromise owing to bupivacaine intoxication in piglets, first-line rescue with epinephrine was more effective than Intralipid with regard to survival as well as normalization of hemodynamic parameters and ET (CO2) [30].

Intravenous lipid emulsion (ILE) has been proposed as a rescue therapy for severe local anesthetic drugs toxicity, but experience is limited with other lipophilic drugs. An 18-year-old healthy woman was admitted 8 h after the voluntary ingestion of sustained-release diltiazem (3600 mg), with severe hypotension refractory to fluid therapy, calcium salts, and high-dose norepinephrine (6.66 μ g/ kg/min). Hyperinsulinemia Euglycemia therapy was initiated and shortly after was followed by a protocol of ILE (intralipid 20%, 1.5 ml/kg as bolus, followed by 0.25 ml/kg over 1h). The main finding attributed to ILE was an apparent rapid decrease in insulin resistance, despite a prolonged serum diltiazem elimination half-life. Diltiazem is a lipophilic cardio toxic drug, which could be sequestered in an expanded plasma lipid phase. The mechanism of action of ILE is not known, including its role in insulin resistance and myocardial metabolism in calcium-channel blocker poisoning [31].

Linoleic Acid (Main Component in Le)-Brain Mitochondria Interaction

Linoleic acid (LA; 18:2 n-6), the most abundant polyunsaturated fatty acid in the US diet, is a precursor to oxidized metabolites that have unknown roles in the brain. Here, we show that oxidized LA-derived metabolites accumulate in several rat brain regions during CO2-induced ischemia and that LA-derived 13-hydroxyoctadecadienoic acid, but not LA, increase somatic paired-pulse facilitation in rat hippocampus by 80%, suggesting bioactivity. This study provides new evidence that LA participates in the response to ischemia-induced brain injury through oxidized metabolites that regulate neurotransmission. Targeting this pathway may be therapeutically relevant for ischemiarelated conditions such as stroke [32].

Long-chain polyunsaturated fatty acids like conjugated linoleic acids (CLA) are required for normal neural development and cognitive function and have been ascribed various beneficial functions. Recently, oral CLA also has been shown to increase testosterone (T) biosynthesis, which is known to diminish traumatic brain injury (TBI)-induced neuropathology and reduce deficits induced by stroke in adult rats. To test the impact of CLA on cognitive recovery following a TBI, 5-6 month old male Sprague Dawley rats received a focal injury (craniectomy+controlled cortical impact (CCI; n=17)) or Sham injury (craniectomy alone; n=12) and were injected with 25 mg/kg body weight of Clarinol® G-80 (80% CLA in safflower oil; n=16) or saline (n=13) every 48 hrs for 4 weeks. Sham surgery decreased baseline plasma progesterone (P4) by 64.2% (from 9.5 ± 3.4 ng/mL to 3.4 ± 0.5 ng/mL; p=0.068), T by 74.6% (from 5.9 ± 1.2 ng/mL to 1.5 ± 0.3 ng/mL; p<0.05), 11-deoxycorticosterone (11-DOC) by 37.5% (from 289.3 ± 42.0 ng/mL to 180.7 ± 3.3 ng/mL), and corticosterone by 50.8% (from 195.1 ± 22.4 ng/mL to 95.9 ± 2.2 ng/mL), by post-surgery day 1. CCI injury induced similar declines in P4, T, 11-DOC and corticosterone (58.9%, 74.6%, 39.4% and 24.6%, respectively) by post-surgery day 1. These results suggest that both Sham surgery and CCI injury induce hypogonadism and hypo-adrenalism in adult male rats. CLA treatment did not reverse hypogonadism in Sham (P4: 2.5 ± 1.0 ng/mL; T: 0.9 ± 0.2 ng/mL) or CCIinjured (P4: 2.2 ± 0.9 ng/mL; T: 1.0 ± 0.2 ng/mL, p>0.05) animals by post-injury day 29, but rapidly reversed by postinjury day 1 the hypo-adrenalism in Sham (11-DOC: 372.6 ± 36.6 ng/mL; corticosterone: 202.6 ± 15.6 ng/mL) and CCI-injured (11-DOC: 384.2 ± 101.3 ng/mL; corticosterone: 234.6 ± 43.8 ng/mL) animals. In Sham surgery animals, CLA did not alter body weight, but did markedly increase latency to find the hidden Morris Water Maze platform (40.3 ± 13.0s) compared to saline treated Sham animals (8.8 ± 1.7s). In CCI injured animals, CLA did not alter CCI-induced body weight loss, CCI-induced cystic infarct size, or deficits in rotarod performance. However, like Sham animals, CLA injections exacerbated the latency of CCI-injured rats to find the hidden MWM platform (66.8 ± 10.6 s) compared to CCIinjured rats treated with saline (30.7 ± 5.5 s, p<0.05). These results indicate that chronic treatment of CLA at a dose of 25 mg/kg body weight in adult male rats over 1-month 1) does not reverse craniectomy- and craniectomy + CCIinduced hypogonadism, but does reverse craniectomyand craniectomy + CCI-induced hypo-adrenalism, 2) is detrimental to medium- and long-term spatial learning and memory in craniectomized uninjured rats, 3) limits cognitive recovery following a moderate-severe CCI injury, and 4) does not alter body weight [33].

Oxidative damage of membrane polyunsaturated fatty acids (PUFA) is thought to play a major role in mitochondrial dysfunction related to Parkinson's disease (PD). The toxic products formed by PUFA oxidation inflict further damage on cellular components and contribute to neuronal degeneration. Here, we tested the hypothesis that isotopic reinforcement, by de-uteration of the bisallylic sites most susceptible to oxidation in PUFA may provide at least partial protection against nigrostriatal injury in a mouse model of oxidative stress and cell death, the 1-methyl-4-phenyl- 1,2,3,6-tetrahydropyridine (MPTP) model. Mice were fed a fat-free diet supplemented with saturated acids, oleic acid and essential PUFA: either normal, hydrogenated linoleic (LA, 18:2n-6) and α -linolenic (ALA, 18:3n-3) or deuterated 11,11-D2-LA and 11,11,14,14-D4-ALA in a ratio of 1:1 (to a total of 10% mass fat) for 6 days; each group was divided into two cohorts receiving either MPTP or saline and then continued on respective diets for 6 days. Brain homogenates from mice receiving deuterated PUFA (D-PUFA) vs. hydrogenated PUFA (H-PUFA) demonstrated a significant incorporation of deuterium as measured by isotope ratio mass-spectrometry. Following MPTP exposure, mice fed H-PUFA revealed 78.7% striatal dopamine (DA) depletion compared to a 46.8% reduction in the D-PUFA cohort (as compared to their respective saline-treated controls), indicating a significant improvement in DA concentration with D-PUFA. Similarly, higher levels of the DA metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) were detected in MPTP-exposure mice administered D-PUFA; however, saline-treated mice revealed no change in DA or DOPAC levels. Western blot analyses of tyrosine hydroxylase (TH) confirmed neuroprotection with D-PUFA, as striatal homogenates showed higher levels of TH immune-reactivity in D-PUFA (88.5% control) vs. H-PUFA (50.4% control) in the MPTP-treated cohorts. In the substantia nigra, a significant improvement was noted in the number of nigral dopaminergic neurons following MPTP exposure in the D-PUFA (79.5% control) vs. H-PUFA (58.8% control) mice using unbiased stereological cell counting. Taken together, these findings indicate that dietary isotopic reinforcement with D-PUFA partially protects against nigrostriatal damage from oxidative injury elicited by MPTP in mice [34].

Arachidonic acid (AA), 5,8,11,14-eicosateraenoic acid is abundant, active and necessary in the human body. In the present study, we reported the neuroprotective effects and mechanism of arachidonic acid on hippocampal slices insulted by glutamate, NaN3 or H2O2 in vitro. Different types of models of brain injury in vitro were developed by 1mM glutamate, 10mM NaN3 or 2mM H2O2. After 30 min of preincubation with arachidonic acid or linoleic acid, hippocampal slices were subjected to glutamate, NaN3 or H2O2, then the tissue activities were evaluated by using the 2,3,5-triphenyltetrazolium chloride method. Endogenous antioxidant enzymes activities (SOD, GSH-PX and catalase) in hippocampal slices were evaluated during the course of incubation. MK886 (5 microM; a noncompetitive inhibitor of proliferator-activated receptor [PPAR]alpha), BADGE (bisphenol A diglycidyl ether; 100 microM; an antagonist of PPARgamma) and cycloheximide (CHX; 30 microM; an inhibitor of protein synthesis) were tested for their effects on the neuroprotection afforded by arachidonic acid. Population spikes were recorded in randomly selected hippocapal slices. Arachidonic acid (1-10 microM) dose dependently protected hippocampal slices from glutamate and H2O2 injury (P<0.01), and arachidonic acid (10 microM) can significantly improve the activities of Cu/Zn-SOD in hippocampal slices after 1h incubation. In addition, 10 microM arachidonic acid significantly increased the activity of Mn-SOD and catalase, and decreased the activities of Cu/Zn-SOD to control value after 3h incubation. These secondary changes of SOD during incubation can be reversed by indomethacine (10 microM; a nonspecific cyclooxygenase inhibitor) or AA 861 (20 microM; a 5-lipoxygenase inhibitor). Its neuroprotective effect was completely abolished by BADGE and CHX. These observations reveal that arachidonic acid can defense against oxidative stress by boosting the internal antioxidant system of hippocampal slices. Its neuroprotective effect may be mainly mediated by the activation of PPARgamma and synthesis of new protein in tissue [35].

Free fatty acid (FFA) concentrations in cerebrospinal fluid (CSF) are recognized as markers of brain damage in animal studies. There is, however, relatively little information regarding FFA concentrations in human CSF in normal and pathological conditions. The present study examined FFA concentrations in CSF from 15 patients with traumatic brain injury (TBI) and compared the data with values obtained from 73 contemporary controls. Concentrations of specific FFAs from TBI patients, obtained within 48 h of the insult were significantly greater than those in the control group (arachidonic, docosahexaenoic and myristic, P<0.001; oleic, palmitic, P<0.01; linoleic, P<0.05). Higher concentrations of total polyunsaturated fatty acids (P<0.001) and of arachidonic, myristic and palmitic acids measured individually in CSF (P<0.01) obtained 1 week after the insult were associated with a worse outcome at the time of hospital discharge using the Glasgow Outcome Scale. This preliminary investigation suggests that CSF FFA concentrations may be useful as a predictive marker of outcome following TBI [36].

Elevated levels of free fatty acids (FFA) have been implicated in the pathogenesis of neuronal injury and death induced by cerebral ischemia. This study evaluated the effects of immune-suppressants agents, calcineurin inhibitors and blockade of endoplasmic reticulum (ER) calcium channels on free fatty acid formation and efflux in the ischemic/reperfused (I/R) rat brain. Changes in the extracellular levels of arachidonic, docosahexaenoic, linoleic, myristic, oleic

four-vessel occlusion-elicited global cerebral ischemia were examined using a cortical cup technique. A 20-min period of ischemia elicited large increases in the efflux of all six FFAs, which were sustained during the 40 min of reperfusion. Cyclosporin A (CsA) and trifluoperazine, which reportedly inhibit the I/R elicited opening of a mitochondrial permeability transition (MPT) pore, were very effective in suppressing ischemia/reperfusion evoked release of all six FFAs. FK506, an immunosuppressant which does not directly affect the MPT, but is a calcineurin inhibitor, also suppressed the I/R-evoked efflux of FFAs, but less effectively than CsA. Rapamycin, a derivative of FK506 which does not inhibit calcineurin, did not suppress I/R-evoked FFA efflux. Gossypol, a structurally unrelated inhibitor of calcineurin, was also effective, significantly reducing the efflux of docosahexaenoic, arachidonic and oleic acids. As previous experiments had implicated elevated Ca2+ levels in the activation of phospholipases with FFA formation, agents affecting endoplasmic reticulum stores were also evaluated. Dantrolene, which blocks the ryanodine receptor (RyR) channel of the ER, significantly inhibited I/R-evoked release of docosahexaenoic, arachidonic, linoleic and oleic acids. Ryanodine, which can either accentuate or block Ca2+ release, significantly enhanced ischemia/reperfusionelicited efflux of linoleic acid, with non-significant increases in the efflux of myristic, arachidonic, palmitic and oleic acids. Xestospongin C, an inhibitor of the inositol triphosphate (IP3R) channel, failed to affect I/R-evoked FFA efflux. Thapsigargin, an inhibitor of the Ca2+-ATPase ER uptake pump, elicited significant elevations in the efflux of myristic, arachidonic and linoleic acids, in the absence of ischemia. Collectively, the data suggest an involvement of both ER and mitochondrial Ca2+ stores in the chain of events which lead to PLA2 activation and FFA formation [37].

Brain extracellular levels of glutamate, aspartate, GABA and glycine increase rapidly following the onset of ischemia, remain at an elevated level during the ischemia, and then decline over 20-30 min following reperfusion. The elevated levels of the exocytotoxic amino acids, glutamate and aspartate, are thought to contribute to ischemia-evoked neuronal injury and death. Calcium-evoked exocytotic release appears to account for the initial (1-2 min) efflux of neurotransmitter-type amino acids following the onset of ischemia, with non-vesicular release responsible for much of the subsequent efflux of these and other amino acids, including taurine and phosphor-ethanolamine. Extracellular Ca2+-independent release is mediated, in part by Na+- dependent amino acid transporters in the plasma membrane operating in a reversed mode, and by the opening of swellinginduced chloride channels, which allow the passage of amino acids down their concentration gradients. Experiments on cultured neurons and astrocytes have suggested that it is the astrocytes which make the primary contribution to this amino acid efflux. Inhibition of phospholipase A2 attenuates ischemia-evoked release of both amino and free fatty acids from the rat cerebral cortex indicating that this group of enzymes is involved in amino acid efflux, and also accounting for the consistent ischemia-evoked release of phosphorethanolamine. It is, therefore, possible that disruption of membrane integrity by phospholipases plays a role in amino acid release. Recovery of amino acid levels to pre ischemic levels requires their uptake by high affinity Na+-dependent transporters, operating in their normal mode, following restoration of energy metabolism, cell resting potentials and ionic gradients [38].

Free fatty acid (FFA) elevation in the brain has been shown to correlate with the severity of damage in ischemic injury. The etiology of this increase in FFA remains unclear and has been hypothesized to result from phospholipase activation. This study examines the effects of specific phospholipase inhibitors on FFA efflux during ischemia-reperfusion injury. A four-vessel occlusion model of cerebral ischemia was utilized to assess the effects of PLA2 and PLC inhibitors on FFA efflux from rat cerebral cortex. In addition, FFA efflux from non-ischemic cortices exposed to PLA2 and PLC was measured. Concentrations of arachidonic, docosahexaenoic, linoleic, myristic, oleic, and palmitic acids in cortical superfusates were determined using high performance liquid chromatography (HPLC). Exposure to the non-selective PLA2 inhibitor 4-bromophenylacyl bromide (BPB) significantly inhibited FFA efflux during ischemia-reperfusion injury (P<0.01 arachidonic, oleic and palmitic; P<0.05 all others); exposure to the PLC inhibitor U73122 had no observed effect. The effects of the Ca2+-dependent PLA2 inhibitor arachidonyl trifluoromethyl ketone (AACOCF3) mirrored the effects of BPB and led to reductions in all FFA levels (P<0.01 arachidonic, oleic and palmitic; P<0.05 all others). Exposure to the secretory PLA2 inhibitor 3-(3-acetamide-1-benzyl-2- ethyl-indolyl-5-oxy) propane sulfonic acid (LY311727) and to the Ca2+-independent PLA2 inhibitor bromoenol lactone (BEL) had only minimal effects on FFA efflux. Application of both PLA2 and PLC to non-ischemic cortices resulted in significant increases in efflux of all FFA (P<0.05). The study suggests that FFA efflux during ischemia-reperfusion injury is coupled to activation of Ca2+-dependent PLA2 and provides further evidence of the potential neuroprotective benefit of Ca2+-dependent PLA2 inhibitors in ischemia [39].

Conclusion

The 4 case reports in this article describing the successful use of lipid emulsions (Smoflipid 20% and Lipidem 20%) are the first case reports of Lipid Emulsion Treatment (LET) of Post-operative cognitive dysfunction (POCD) in the medical literature.

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### Local Anesthesia Reversal (LAR) of Spinal Anesthesia by Lipid Emulsion (Lipofundin 20%) for Day Case Surgery

_List of Author(s): Joseph Eldor, Kien NT._

Abstract

A 46 years old Male was diagnosed with penis fracture due to sexual intercourse. A 72 years old Male was diagnosed as having a tumor on the upper pole of the femur.A 41 years old Female had a Cesarean section. All of them underwent spinal anesthesia for their operations. All of them underwent at the end of their operations Local anesthesia reversal (LAR) of Spinal anesthesia by Lipid Emulsion (Lipofundin 20%) using Bolus and Infusion. The local anesthesia reversal was started in approximately 3 minutes after starting the bolus injection and completed in approximately 30 minutes afterwards.This new modality of LAR can make a great change in the use of spinal anesthesia in day case surgery facilities.

Keywords:

Day case surgery, Bupivacaine, Intralipid,Lipofundin, Lipid emulsion, LE, Spinal anesthesia, Local anesthesia reversal, LAR.

Case Reports

Case no. 1

A 46 years old Male was diagnosed with penis fracture due to sexual intercourse. He underwent an emergency surgery for penis repair on 21.2.2018 at the Military Hospital 103, Vietnam Military Medical University. The patient was anesthetized by spinal anesthesia with 8 mg of bupivacaine plus 20 mcg fentanyl in the sitting position at the L2-L3 level. The point time of the spinal block was15h 35 min.

Onset time: 3 mins.

Anesthesia effect was very good for the surgery.

Dermatome check by the cold test with alcohol gauze was T$ at 10 mins after the spinal block.

Duration of surgery: 30 mins.

Hemodynamic was stable during the surgery.

Surgery was completed at 16h 15min (50 mins after the performance of the spinal block).

Lipid emulsion (Lipofundin 20%)bolus injection was started at 16h 15 mins over 3 mins with the dose of 1.5 mg/kg (patient's weight 68 kg), then by continuous infusion with 0.25 ml/kg/min over 12 mins.Total volume of the Lipid emulsion was 300ml. The patient was monitored closely during the local anesthesia reversal (LAR) process(Table 1).

Table 1

Videos:

Starting the bolus of lipofundin 20% injection: https://youtu.be/ cXIylBqO8CA

1 minute after finishing bolus lipofundin injection: https://youtu.be/ic9xoODVqXc

2 minutes after finishing bolus lipofundin injection: https://youtu.be/BcPdXevSKvI

19 minutes after finishing bolus lipofundin injection: https://youtu.be/FJpl22JFSEc

28 minutes after finishing bolus lipofundin injection: https://youtu.be/9cxuynCwrvY

32 minutes after finishing bolus lipofundin injection: https://youtu.be/5GuxnVucjzY

34 minutes after finishing bolus lipofundin injection: https://youtu.be/yQuk2EEcNqM

39 minutes after finishing bolus lipofundin injection: https://youtu.be/Rx8dCQPjXuY

42 minutes after finishing bolus lipofundin injection: https://youtu.be/E85Xv2gfGOY

47 minutes after finishing bolus lipofundin injection: https://youtu.be/GygRH6GYbW0

48 minutes after finishing bolus lipofundin injection: https://youtu.be/25eBCScsVbk

50 minutes after finishing bolus lipofundin injection: https://youtu.be/IBacn8MrbJU

52 minutes after finishing bolus lipofundin injection: https://youtu.be/oleWEpuNZ5I

61 minutes after finishing bolus lipofundin injection: https://youtu.be/AKt23S6FPpk

69 minutes after finishing bolus lipofundin injection: https://youtu.be/ipWH95V4e0k

73 minutes after finishing bolus lipofundin injection: https://youtu.be/WC-bKjpAmmg

Case no. 2

A 72 years old Male was diagnosed as having a tumor on the upper pole of the femur. The patient performed a biopsy on March 9th, 2018 at the Military Hospital 103, Vietnam Military Medical University. The patient was anesthetized by spinal anesthesia with 9 mg of bupivacaine plus 20 mcg fentanyl in the sitting position at L2-L3 level. Point time of the spinal block: 9h 02, AM.

Anesthesia effect was very good for the surgery.

Onset time: 4 mins.

Dermatome check by cold test with alcohol gauze was T4 at 10 mins after the spinal block.

Duration of surgery: 28 mins

Hemodynamic was stable during the surgery.

Surgery was completed at 9h40 which means 38 mins after the spinal block.

Lipid emulsion (Lipofundin 20%) bolus injection was started at 9h50 mins over 3 mins with the dose of 1.5 mg/kg (patient's weight 70kg), then continuous infusion with 175 ml over 30 mins (~0.08 mg/kg/min). Total volume of Lipid emulsion (Lipofundin 20%) was 275ml. The patient was monitored closely in the operating theatre during the lipid emulsion treatment.

Only 3 minutes after finishing the bolus injection the patient could move slightly both legs. The patient got a full recovery of his movement function at 30 minutes after finishing the bolus of Lipofundin 20% injection(Table2).

Videos:

Starting bolus injection:

<https://youtu.be/bBYHP-iFmZI>

https://youtu.be/mVKwwlEfP8A

2 minutes after finishing bolus lipofundin injection: https://youtu.be/63-EeqC7WL8

4 minutes after finishing bolus lipofundin injection: https://youtu.be/6kj5OzFNTwQ

5 minutes after finishing bolus lipofundin injection: https://youtu.be/nM3qjveWQOw

6 minutes after finishing bolus lipofundin injection: https://youtu.be/EN4mKejZItM

7 minutes after finishing bolus lipofundin injection: https://youtu.be/2lrZ82wcYk4

9 minutes after finishing bolus lipofundin injection: https://youtu.be/cpTLMObFRn8

13 minutes after finishing bolus lipofundin injection: https://youtu.be/CBx-O5WQY4Y

30 minutes after finishing bolus lipofundin injection: https://youtu.be/bfi5AGjVcLc

32 minutes after finishing bolus lipofundin injection: https://youtu.be/vqjvxAO6bjA

35 minutes after finishing bolus lipofundin injection: https://youtu.be/NRxzoOr15Z0

48 minutes after finishing bolus lipofundin injection: https://youtu.be/q7Nt_xyBIqk

69 minutes after finishing bolus lipofundin injection: https://youtu.be/ThRqH00mwmo

74 minutes after finishing bolus lipofundin injection: https://youtu.be/PuUdmVpmkKo

A 41 years old Female had a Cesarean section on March 15th, 2018 at the Military Hospital 103, Vietnam Military Medical University. The patient was anesthetized by spinal anesthesia with 8 mg of bupivacaine plus 20 mcg fentanyl in the left lateral position at L2-L3 level. Point time of spinal block: 11h AM.

• Onset time: 3 mins.

• Anesthesia effect was very good for surgery.

• Case Reports T3 at 10 mins after the spinal block.

• Duration of surgery: 50 mins.

• Hemodynamic was stable during the surgery.

• Surgery was completed at 11h55, meaning at 60 mins after the spinal block.

Lipid emulsion (Lipofundin 20%) bolus injection was started at 12h05 mins over 3 mins with the dose of 1.5 mg/ kg (patient's weight 60kg), then continuous infusion with 150 mi LE over 10 mins (0.25 mg/kg/min). Total volume of Lipid emulsion was 250ml. Patient was monitored closely in the operating theatre during the LE treatment.

Table 2

Only 1-2 minutes after starting the bolus injection,the patient could move slightly the right foot. The left foot could be moved slightly after finishing the bolus of the Lipofundin 20% injection at 8 mins. The patient got a full recovery movement function at 48 minutes after finishing the bolus Lipofundin injection without any pain (VAS=0) although sensory block was reduced to T12(Table 3).

Table 3

Videos:

Starting bolus lipofundin injection: https://youtu.be/ szUw4o3R3Oo

1 minute after starting bolus injection: https://youtu.be/ LSSI5v9Tu-w

Finish bolus lipofundin injection: https://youtu.be/PIhxJ3- zfA

1 minute after finishing bolus injection: https://youtu. be/FNKKJU0VWOo

2 minutes after finishing bolus injection: https://youtu. be/xjS_PjtFpzY

4 minutes after finishing bolus injection: https://youtu. be/PDGEQYj1lxY

5 minutes after finishing bolus injection: https://youtu. be/9TZGxqC-G0A

7 minutes after finishing bolus injection: https://youtu. be/mzR96YM637g

8 minutes after finishing bolus injection: https://youtu. be/pfVsS2ChjAI

10 minutes after finishing bolus injection: https://youtu. be/roGW5YOAbK8

11 minutes after finishing bolus injection: https://youtu. be/QvZrAqBcBnY

12 minutes after finishing bolus injection: https://youtu. be/ejFnL4rPamQ

15 minutes after finishing bolus injection: https://youtu. be/vOk8LoBDHvo

18 minutes after finishing bolus injection: https://youtu. be/ucmm8nfFqeo

21 minutes after finishing bolus injection: https://youtu. be/msGDpCzQrIs

25 minutes after finishing bolus injection: https://youtu.be/2L335DHPd-k

28 minutes after finishing bolus injection: https://youtu. be/Vo4vNlcgfV8

31 minutes after finishing bolus injection: https://youtu. be/sW0TI8PJSMk

43 minutes after finishing bolus injection: https://youtu. be/YjNbSJuwd4Q

45 minutes after finishing bolus injection: https://youtu. be/auPwEHaMMO8

48 minutes after finishing bolus injection: https://youtu. be/ZRFH2B7oDxk

59 minutes after finishing bolus injection: https://youtu. be/EQs5ggSEEls

62 minute2 after finishing bolus injection: https://youtu. be/L4U-WrQ6qnQ

Discussion

Corning, a neurologist, was the first to attempt spinal anesthesia, although not in any way as we understand it today[1]. He was under the false impression that injecting cocaine between the spinous processes would result in rapid transportation of the drug to the spinal cord, thus producing anesthesia of the cord. Corning's experiments were carried out in a man and a dog. The man, receiving approximately 120 mg of cocaine which is about four times the lethal dose, was certainly lucky to survive the experiment and what was achieved was probably epidural anesthesia [2]; the dog,receiving approximately 13 mg, presumably had spinal anesthesia[2].

Both general and spinal anaesthesia with short-acting local anaesthetics are suitable and reliable for knee arthroscopy as an ambulatory procedure. Chloroprocaine (CP) 1% seems to be the ideal spinal local anaesthetic for this indication.

The aim of this study was to compare spinal anaesthesia using CP 1% with general for outpatient knee arthroscopy with regard to procedure times, occurrence of pain, patient satisfaction and recovery, and also costs[3].

A randomised controlled single-centre trial.University Medical Centre Mannheim, Department of Anaesthesiology and Surgical Intensive Care Medicine, Mannheim, Germany. April 2014 to August 2015.

A total of 50 patients (women/men, 18 to 80 years old, ASA I to III) undergoing outpatient knee arthroscopy were included. A contra-indication to an allocated anaesthetic technique or an allergy to medication required in the protocol led to exclusion.

Either general anaesthesia with sufentanil, propofol and a laryngeal mask for airway-management or spinal with 40- mg CP 1% were used. We noted procedure times, patient satisfaction/recovery and conducted a 7-day follow-up[3].

Primary outcome was duration of stay in the day-surgery centre. Secondary outcomes were first occurrence of pain, patient satisfaction, quality of recovery and adverse effects. In addition, we analysed treatment costs.

Spinal had faster recovery than general anaesthesia with patients reaching discharge criteria significantly earlier [117 min (66 to 167) versus 142 min (82 to 228), P = 0.0047]. Pain occurred significantly earlier in the general anaesthesia group (P = 0.0072). Costs were less with spinal anaesthesia (cost ratio spinal: general 0.57). Patients felt significantly more uncomfortable after general anaesthesia (P = 0.0096). Spinal anaesthesia with 40mg CP 1% leads to a significantly earlier discharge and is cheaper compared with general[3].

Bupivacaine is an amide local anesthetic with a slow onset (5-10 minutes, longer with isobaric forms). It is a long acting spinal anesthetic appropriate for procedures that last 2-2.5 hours. It is comparable to tetracaine; however, tetracaine exhibits a more profound motor block and increased duration when vasoconstrictors are added. Available hyperbaric forms include concentrations of 0.5% and 0.75%, with dextrose 8.25%. Isobaric formulations are available in concentrations of 0.5% and 0.75%. When using isobaric solutions, the total mg dose is more important than the total volume of medication administered.

Spinal anesthesia (SPA) has not been popular for daycase surgery because of prolonged neurologic blockade with long-acting local anesthetics such as bupivacaine, thereby delaying discharge. Although the intermediate duration of action of lidocaine and mepivacaine appears to be more suitable for day-case surgery, their use is not deemed appropriate by many because of a high incidence of transient neurologic symptoms (TNSs).

Prilocaine has a similar intrathecal pharmacokinetic profile as lidocaine but with a significantly lower risk of TNSs. Onset of spinal after 2-chloroprocaine is comparable with lidocaine or prilocaine, but with a considerably shorter duration of action. Also, TNS is clearly less frequent compared with lidocaine. Although its intrathecal use has recently been approved in Europe, this is still considered to be off-label in the USA. Articaine provides an extraordinary fast onset and a short duration of spinal block, the latter being approximately intermediate between chloroprocaine and prilocaine. However, articaine is associated with a high risk for intraoperative hypotension and a small risk for TNS, albeit but less frequent than after lidocaine. Concerns regarding possible neurotoxicity of articaine remain to be resolved.

SPA for day cases might become a most valuable method for ambulatory surgery when using short acting local anesthetics. This, however, not only depends on drugs being used but also on infrastructure (post anaesthesia care unit) and organizational issues[4].

An increasing number of day-case surgical patients is challenging the presently used methods of anaesthesia: reliable surgical anaesthesia should be fast, with rapid recovery and minimal side effects. To compete with modern ambulatory general anaesthesia a knowledge of special spinal anaesthesia techniques is essential. For surgical procedures in one lower limb, a low dose of hyperbaric bupivacaine with standardized spinal anaesthesia technique produces a reliable block, with low incidence of side effects and home-readiness equal to spinal anaesthesia with lidocaine (50 mg) or general anaesthesia (desflurane), whereas ropivacaine has not shown benefits over spinal anaesthesia with bupivacaine. 'Walk-in, walk-out' spinals with an extremely low dose of lidocaine and opioids for gynaecological laparoscopy created the concept of selective spinal anaesthesia. Reintroduction of chloroprocaine may provide a solution for bilateral, short-acting spinal anaesthesia in the future.

To produce reliable spinal anaesthesia with a reasonable recovery time it is essential to understand the factors affecting the spread of spinal block and to choose the optimal drug and adequate dose for specific surgical procedures[5].

The local anaesthetics used in day-case spinal anaesthesia should provide short recovery times. We aimed to compare hyperbaric prilocaine and bupivacaine in terms of sensory block resolution and time to home readiness in day-case spinal anaesthesia[6]. Fifty patients undergoing perianal surgery were randomized into two groups. The bupivacainefentanyl group (Group B) received 7.5 mg, 0.5% hyperbaric bupivacaine+20 μg fentanyl in total 1.9 mL. The prilocainefentanyl group (Group P) received 30 mg, 0.5% hyperbaric prilocaine+20 μg fentanyl in the same volume.

Time to L1 block and maximum block was shorter in Group P than in Group B (Group P 4.6 ± 1.3 min versus Group B 5.9 ± 01.9 min, P=0.017, and Group P 13.2 ± 7.5 min versus Group B 15.3 ± 6.6 min, P=0.04). The time to L1 regression and S3 regression of the sensorial block was significantly shorter in Group P than in Group B (45.7 ± 21.9 min versus 59.7 ± 20.9 min, P=0.024, and 133.8 ± 41.4 min versus 200.4 ± 64.8 min,P<0.001). The mean time to home readiness was shorter for Group P than for Group B (155 ± 100.2 min versus 207.2 ± 62.7 min (P<0.001)).

Day-case spinal anaesthesia with hyperbaric prilocaine + fentanyl is superior to hyperbaric bupivacaine in terms of earlier sensory block resolution and home readiness and the surgical conditions are comparable for perianal surgery[6].

The incidence of perianal surgery varies among institutions, accounting for up to 10% of general surgical procedures[7]. The procedure is suitable to perform on a day-case basis with spinal anaesthesia[8,9]. However, prolonged sensory and motor block and urinary retention can cause a delay in discharge[10,11]. Day-case spinal anaesthesia with short-acting local anaesthetics such as lidocaine and chloroprocaine can provide short times to discharge[12,13]. However, the association of lidocaine with transient neurologic symptoms (TNS) and chloroprocaine with neurologic injury has limited the use of these agents in spinal anaesthesia[14,15]. Bupivacaine is safe with a very low incidence of associated TNS, but the prolonged sensory and motor block are a disadvantage for day-case spinal anaesthesia[16]. The use of small doses of bupivacaine with the addition of opioids is proposed to enhance the recovery of the spinal block [17].

Spinal anaesthesia when compared to general anaesthesia has been shown to decrease postoperative morbidity in orthopaedic surgery. The aim of the present study was to assess the differences in thirty-day morbidity and mortality for patients undergoing hip fracture surgery with spinal versus general anaesthesia[18].

The American College of Surgeons National Surgical Quality and Improvement Program (NSQIP) database was used to identify patients who underwent hip fracture surgery with general or spinal anaesthesia between 2010 and 2012 using CPT codes 27245 and 27244. Patient characteristics, complications, and mortality rates were compared. Univariate analysis and multivariate logistic regression were used to identify predictors of thirty-day complications. Stratified propensity scores were employed to adjust for potential selection bias between cohorts.

6133 patients underwent hip fracture surgery with spinal or general anaesthesia; 4318 (72.6%) patients underwent fracture repair with general anaesthesia and 1815 (27.4%) underwent fracture repair with spinal anaesthesia. The spinal anaesthesia group had a lower unadjusted frequency of blood transfusions (39.34% versus 45.49%; p<0.0001), deep vein thrombosis (0.72% versus 1.64%; p=0.004), urinary tract infection (8.87% versus 5.76%; p<0.0001), and overall complications (45.75% versus 48.97%; p=0.001). The length of surgery was shorter in the spinal anaesthesia group (55.81 versus 65.36 min; p<0.0001). After multivariate logistic regression was used to adjust for confounders, general anaesthesia (odds ratio, 1.29; 95% confidence interval, 1.14-1.47; p=0.0002) was significantly associated with increased risk for complication after hip fracture surgery. Age, female sex, body mass index, hypertension, transfusion, emergency procedure, operation time, and ASA score were risk factors for complications after hip fracture repair (all p<0.05).

Patients who underwent hip fracture surgery with general anaesthesia had a higher risk of thirty-day complications as compared to patients who underwent hip fracture repair with spinal anaesthesia. Surgeons should consider using spinal anaesthesia for hip fracture surgery[18].

Spinal anaesthesia is an easy and reliable technique. Factors limiting its use in the ambulatory setting include delayed ambulation, risk of urinary retention and pain after block regression. On the contrary, general anaesthesia with fast-acting drugs provides a fast recovery that facilitates an early discharge. Although recovery after spinal anaesthesia has been improved by reducing the dose of the commonly used long acting local anaesthetics, discharge times are still prolonged compared with general anaesthesia. 2-Chloroprocaine is an amino-ester local anaesthetic with a very short half-life and a favourable evolution of spinal block for ultra-short outpatient procedures. Moreover, the preservative free 2-chloroprocaine solution showed a very low risk of urinary retention and transient neurological symptoms when compared with bupivacaine and lidocaine[19].

We compared the costs related to the clinical effectiveness of general anesthesia versus spinal anesthesia in inguinal hernioplasty ambulatory surgery[20].An observational, retrospective cohort study measurement and analysis of cost-effectiveness, in the ambulatory surgery unit of a general hospital. All patients over 18 years of age diagnosed with primary inguinal hernia and scheduled for unilateral hernioplasty between January 2010 and December 2011 were included. Duration of anesthetic induction, length of stay in both the operating room, and in the post-anesthesia care unit, the anesthetic effectiveness (the incidence of adverse effects and the patient's comfort level), and variable economic costs associated with the use of drugs, as well as the use of human resources, were compared.

The final analysis included 218 patients, 87.2% male, with a mean age of 53 years (range: 18-85 years). Of these, 139 (63.76%) received subarachnoid anesthesia and 79(36.2%) general anesthesia. The length of time a patient remained in the post-anesthesia care unit was 337.6±160.2min in the subarachnoid anesthesia group, and 210.0±97.5min for the general anesthesia group (P<0.001). Costs of drugs for general anesthesia were higher than that for subarachnoid anesthesia (86.2±8.3 vs. 18.7±7.2). The total cost difference between the 2 techniques was €115.8 more for subarachnoid anesthesia (P<0.001).

Both techniques showed similar effectiveness. The overall costs for subarachnoid anesthesia were greater than for the general. The cost-effectiveness of general anesthesia is better for outpatient inguinal hernia repair surgery[20].

Length of stay after total hip arthroplasty (THA) has decreased over the last two decades. However, published studies that have examined same-day and early discharge protocols after THA have been done in highly selected patient groups operated on by senior surgeons in a nonrandomized fashion without control subjects.

The purpose of this study was to evaluate and compare patients undergoing THA who are discharged on the same day as the surgery ("outpatient," less than 12-hour stay) with those who are discharged after an overnight hospital stay ("inpatient") with regard to the following outcomes: (1) postoperative pain; (2) perioperative complications and healthcare provider visits (readmission, emergency department or physician office); and (3) relative work effort for the surgeon's office staff[21].

A prospective, randomized study was conducted at two high-volume adult reconstruction centers between July 2014 and September 2015. Patients who were younger than 75 years of age at surgery, who could ambulate without a walker, who were not on chronic opioids, and whose body mass index was less than 40 kg/m2 were invited to participate. All patients had a primary THA performed by the direct anterior approach with spinal anesthesia at a hospital facility. Study data were evaluated using an intentionto- treat analysis. A total of 220 patients participated, of whom 112 were randomized to the outpatient group and 108 were randomized to the inpatient group. Of the 112 patients randomized to outpatient surgery, 85 (76%) were discharged as planned. Of the remaining 27 patients, 26 were discharged after one night in the hospital and one was discharged after two nights. Of the 108 patients randomized to inpatient surgery with an overnight hospital stay, 81 (75%) were discharged as planned. Of the remaining 27 patients, 18 met the discharge criteria on the day of their surgery and elected to leave the same day, whereas nine patients stayed two or more nights.

On the day of surgery, there was no difference in visual analog scale (VAS) pain among patients who were randomized to discharge on the same day and those who were randomized to remain in the hospital overnight (outpatient 2.8 ± 2.5, inpatient 3.3 ± 2.3, mean difference -0.5, 95% confidence interval [CI], -1.1 to 0.1,p=0.12). On the first day after surgery, outpatients had higher VAS pain (at home) than inpatients (3.7 ± 2.3 versus 2.8 ± 2.1, mean difference 0.9, 95% CI, 0.3-1.5, p=0.005). With the numbers available, there was no difference in the number of reoperations, hospital readmissions without reoperation, emergency department visits without hospital readmission, or acute office visits. At 4-week follow up, there was no difference in the number of phone calls and emails with the surgeon's office (outpatient: 2.4 ± 1.9, inpatient: 2.4 ± 2.2, mean difference 0, 95% CI, -0.5 to 0.6, p=0.94).

Outpatient THA can be implemented in a defined patient population without requiring additional work for the surgeon's office. Because 24% (27 of 112) of patients planning to have outpatient surgery were not able to be discharged the same day, facilities to accommodate an overnight stay should be available[21].

Conclusion

A 46 years old Male was diagnosed with penis fracture due to sexual intercourse. A 72 years old Male was diagnosed as having a tumor on the upper pole of the femur.A 41 years old Female had a Cesarean section. All of them underwent spinal anesthesia for their operations. All of them underwent at the end of their operations Local anesthesia reversal (LAR) of Spinal anesthesia by Lipid Emulsion (Lipofundin 20%) using Bolus and Infusion. The local anesthesia reversal was started in approximately 3 minutes after starting the bolus injection and completed in approximately 30 minutes afterwards.

This new modality of LAR can make a great change in the use of spinal anesthesia in day case surgery facilities.

It is the first time in the medical literature that spinal anesthesia motor block is successfully reversed by Lipid Emulsion (Lipofundin 20%) bolus and infusion.

References

1. Corning JL (1885) Spinal anaesthesia and local medication of the cord. N.Y.Med.J 42: 483-485. [ Ref ]

2. Fink BR (1980) History of local anesthesia. In: Cousins MJ, Bridenbaugh PO (eds). Neural blockade 1st ed. Philadelphia: JB Lippincott 6-7.  [ Ref ]

3. Gebhardt V, Zawierucha V, Schöffski O, Schwarz A, Weiss C, et al. (2018) Spinal anaesthesia with chloroprocaine 1% versus total intravenous anaesthesia for outpatient knee arthroscopy: A randomised controlled trial. Eur J Anaesthesiol.  [ Ref ]

4. Wulf H, Hampl K, Steinfeldt T (2013) Speed spinal anesthesia revisited: new drugs and their clinical effects. Curr Opin Anaesthesiol 26: 613-620.  [ Ref ]

5. Korhonen AM (2006) Use of spinal anaesthesia in day surgery. Curr Opin Anaesthesiol 19: 612-616.  [ Ref ]

6. Kaban OG, Yazicioglu D, Akkaya T, Sayin MM, Seker D, et al. (2014) Spinal anaesthesia with hyperbaric prilocaine in day-case perianal surgery: randomised controlled trial. Scientific World Journal. [ Ref ]

7. Ergül Z, Akinci M, Ugurlu C, Kaya O, Kulacoglu H, et al. (2012) How did a training hospital change in ten years? Journal of Clinical and Analytical Medicine 3: 320-324.  [ Ref ]

8. Watson B, Howell V (2007) Spinal anaesthesia: the saviour of day surgery? Current Anaesthesia & Critical Care 18: 193-199.  [ Ref ]00078-6/abstract)

9. Zoremba M, Wulf H (2010) Spinal anaesthesia in day case surgery old technique new trends. Anasthesiologie Intensivmedizin Notfallmedizin Schmerztherapie 45: 176-180. [ Ref ]

10. Song D, Greilich NB, White PF, Watcha MF, Tongier WK (2000) Recovery profiles and costs of anesthesia for outpatient unilateral inguinal herniorrhaphy. Anesthesia and Analgesia 91: 876-881.  [ Ref ]

11. Pavlin DJ, Rapp SE, Polissar NL, Malmgren JA, Koerschgen M, et al. (1998) Factors affecting discharge time in adult outpatients. Anesthesia and Analgesia 87: 816-826.  [ Ref ]

12. Kamphuis ET, Kuipers PW, van Venroij GE, Kalkman CJ (2008) The effects of spinal anesthesia with lidocaine and sufentanil on lower urinary tract functions. Anesthesia and Analgesia 107: 2073-2078.  [ Ref ]

13. Sell A, Tein T, Pitkänen M (2008) Spinal 2-chloroprocaine: effective dose for ambulatory surgery. Acta Anaesthesiologica Scandinavica 52: 695-699. [ Ref ]

14. de Weert K, Traksel M, Gielen M, Slappendel R, Weber E, et al. (2000) The incidence of transient neurological symptoms after spinal anaesthesia with lidocaine compared to prilocaine. Anaesthesia 55: 1020-1024.  [ Ref ]

15. Förster JG, Rosenberg PH (2011) Revival of old local anesthetics for spinal anaesthesia in ambulatory surgery. Current Opinion in Anaesthesiology 24: 633-637.  [ Ref ]

16. Gupta A, Axelsson K, Thörn SE, Matthiessen P, Larsson LG, et al. (2003) Low-dose bupivacaine plus fentanyl for spinal anesthesia during ambulatory inguinal herniorrhaphy: a comparison between 6 mg and 7.5 mg of bupivacaine. Acta Anaesthesiologica Scandinavica 47: 13-19.  [ Ref ]

17. Goel S, Bhardwaj N, Grover VK (2003) Intrathecal fentanyl added to intrathecal bupivacaine for day case surgery: a randomized study. European Journal of Anaesthesiology 20: 294-297.  [ Ref ]

18. Fields AC, Dieterich JD, Buterbaugh K, Moucha CS (2015) Short-term complications in hip fracture surgery using spinal versus general anaesthesia. Injury 46: 719-723.  [ Ref ]00078-9/abstract)

19. Fanelli A, Ghisi D, Allegri M (2013) Is spinal anaesthesia a suitable technique for ultra-short outpatient procedures? Acta Biomed 84: 76-80.  [ Ref ]

20. Fernández-Ordóñez M, Tenías JM, Picazo-Yeste J (2014) Spinal anesthesia versus general anesthesia in the surgical treatment of inguinal hernia. Costeffectiveness analysis. Rev Esp Anestesiol Reanim 61: 254-261. [ Ref ]

21. Goyal N, Chen AF, Padgett SE, Tan TL, Kheir MM, et al. (2017) Otto Aufranc Award: A Multicenter, Randomized Study of Outpatient versus Inpatient Total Hip Arthroplasty. Clin Orthop Relat Res 475: 364-372. [ Ref ]

Upper Arm Local Anesthesia Reversal (LAR) Using Lipofundin (3 Case Reports)

List of Author(s): Kien NT, Hien VV, Khanh DT, Joseph Eldor.

Abstract

Local anesthesia reversal(LAR) is a new idea based on the history of Local Anesthetic Systemic Toxicity (LAST). If Intralipid and other specific Lipid emulsions can reverse the cardiac toxicity, why it cannot reverse other features connected to the local anesthesia toxicity?It is a very logical idea. The illogical issue is why it took almost 20 years from the first article on Intralipid and bupivacaine to invent it...?

In our 3 cases the first patient "after finishing the lipofundin bolus injection after 4 mins (137 min after the brachial plexus block), she could move slightly her right finger.The patient could move her hand at 34 mins after the lipofundin bolus injection (166 mins after the brachial plexus block), and she could move her forearm 102 mins after the lipofundin bolus injection".

In the 2nd case "after 80-84 mins of the LE bolus injection (180 min after the brachial plexus block) the patient could move slightly his left thumb.After 184 mins since the lipid emulsion bolus injection (290 mins after the brachial block) the patient could move his hand and arm easily".

In the 3rd case "85-87 mins after the LE bolus injection (220 min after the brachial plexus block), the patient could move slightly his arm. 128 mins after the lipid emulsion bolus injection (261 mins after the brachial plexus block), the patient could move his hand easily".

In all the 3 cases the reversal of the sensory and motor blocks were much faster than in the non-LAR cases as described in the medical literature. In that regards the LAR by Intralipid, Lipofundin and other similar lipid emulsions is a new method for postoperative care of patients after brachial plexus block.

Keywords:

Brachial plexus block, Supraclavicular block,Lipofundin, Intralipid, Lipid emulsion, Local anesthetic systemic toxicity, LAST, Local anesthesia reversal, LAR.

Case Report 1

A 37 years old female was diagnosed an ununion radial bone. She performed a radial bone surgery on 1stMarch 2018 at Military Hospital 103,Vietnam Military Medical University:http://www.csen.com/ upper4.JPG

Patient was anesthetized by ultrasound guided brachial plexus block, upper clavicular approach with lidocaine 4 mg/kg combined with ropivacaine 1mg/kg and epinephrine 1/200.000 in a total volume of 30 ml.

Onset time: 8 mins

Duration of surgery: 100 mins

Anesthesia effect was very good for surgery.Sensory and motor functions of the right hand were assessed before Lipofundin injection and were absent completely after surgery.

Lipid emulsion bolus injection was started at 137 mins after brachial plexus block over 3 mins with the dose of 1.5 mg/kg (patient's weight 65 kg, 158 cm), total -97 ml. Then, continuous infusion with the dose of 0.25ml/kg/min (162ml) over 10 mins was done. Patient was monitored closely.

After finishing the lipofundin bolus injection after 4 mins (137 min after the brachial plexus block), the patient could move slightly her right finger.The patient could move her hand at 34 mins after the lipofundin bolus injection (166 mins after the brachial plexus block),and could move her forearm 102 mins after the lipofundin bolus injection.She completely recovered her movement and sensory 127 mins after the lipofundin bolus injection. Vital signs were stable after the lipofundin injections(Table 1).

Table 1

Videos:

Starting lipofundin bolus injection: https://youtu.be/ rTtDOQiih1U

Continuous lipofundin infusion: https://youtu.be/ lF4bP5zU4Kg

4 mins after finishing lipofundin bolus injection: https:// youtu.be/--TREW5jeTs

13 mins after finishing lipofundin bolus injection: <https://youtu.be/HE80oYqxFjc>

15 mins after finishing lipofundin bolus injection: https://youtu.be/LcPoQrzwxQM

26 mins after finishing lipofundin bolus injection: https://youtu.be/C2-SOngdgWc

34 mins after finishing lipofundin bolus injection: https://youtu.be/xCwbVNuEZ9U

57 mins after finishing lipofundin bolus injection: https://youtu.be/r1fbMnQNLlM

63 mins after finishing lipofundin bolus injection: https://youtu.be/a6JILCUZQSY

67 mins after finishing lipofundin bolus injection: https://youtu.be/j0ALXiaafzc

72 mins after finishing lipofundin bolus injection: https://youtu.be/91cDOiS3rc4

81 mins after finishing lipofundin bolus injection: https://youtu.be/vUS_GJiRjmk

94 mins after finishing lipofundin bolus injection: https://youtu.be/j0zhtChUsBs

104 mins after finishing lipofundin bolus injection: https://youtu.be/ImSV0dmVpg4

111 mins after finishing lipofundin bolus injection: https://youtu.be/EmVxlUtgiJU

131 mins after finishing lipofundin bolus injection: https://youtu.be/U8ywvu_Ny2I

136 mins after finishing lipofundin bolus injection: https://youtu.be/X5IcvySgBMg

139 mins after finishing lipofundin bolus injection: https://youtu.be/cX8Ki4uFhd4

Case report 2

A 19 years old male was diagnosed with two bone fractures in the left forearm due to vehicle accident:http:// www.csen.com/upper3.JPG

He underwent an elective two bone surgery on 27th February, 2018 at the Military Hospital 103,Vietnam Military Medical University. The patient was anesthetized by ultrasound guided brachial plexus block, upper clavicular approach with lidocaine 4 mg/kg combined with ropivacaine 1mg/kg and epinephrine 1/200.000 in total 30 ml of solution.

Onset time: 7 mins.

Duration of surgery: 80 mins.

Anesthesia effect was very good for surgery.Surgery was accomplished in 83 mins after the brachial plexus block. Sensory and motor functions of the left hand were absent completely after the surgery.

Lipid emulsion (Lipofundin) bolus injection was started at point 133 mins after the brachial plexus block over 3 mins with the dose of 1.5 mg/kg (patient's weight is 40kg, 158 cm), total -60 ml. Afterwards a continuous infusion with the dose of 0.25 ml/kg/min (100ml/10 mins) over 10 mins was done. The patient was monitored during the LE infusion until the full recovery of the motor and sensory functions.

After 80-84 mins of the LE bolus injection (180 min after the brachial plexus block) the patient could move slightly his left thumb.After 184 mins since the lipid emulsion bolus injection (290 mins after the brachial block) the patient could move his hand and arm easily.Vital signs were stable during and after the LE bolus and infusion(Table 2).Lipofundin: <http://www.csen.com/Lipofundin.JPG>

Table 2

Videos:

Starting Bolus LE injection: https://youtu.be/ bSUlLPPOOZQ

10 mins after bolus LE injection: https://youtu.be/6VkXsLXlsc

46 mins after bolus LE injection: https://youtu.be/ B8VgbvF8538

60 mins after bolus LE injection: https://youtu.be/ Jc9oCClkHTg

80 mins after bolus LE injection: https://youtu.be/ F7mEXJG_Sdk

84 mins after bolus LE injection: https://youtu.be/ BukCloqzHnU

100 mins after bolus LE injection: https://youtu.be/ VpuUV3A8AcA

102 mins after bolus LE injection: https://youtu.be/ p1CGcsTHzCM

194 mins after bolus LE injection: https://youtu.be/ wfJKDneDj_g

Case report 3

A 49 years old male was diagnosed of a complicated two bone fractures in the right forearm due to labour accident:<http://www.csen.com/upper2.jpg>

The patient performed an elective two bones surgery on 26th Feb, 2018 at the Military Hospital 103, Vietnam Military Medical University. The patient was anesthetized by ultrasound guided brachial plexus block, upper clavicular approach with lidocaine 4 mg/kg combined with ropivacaine 1mg/kg and epinephrine 1/200.000 in total 30 ml of solution.

Onset time: 8 mins.

Duration of surgery: 110 mins.

Anesthesia effect was very good for the surgery.Surgery was accomplished in 120 mins after the brachial plexus block. Sensory and motor functions of the left hand were absent completely after the surgery.

Lipid emulsion (Lipofundin) bolus injection was started at the point of 133 mins after the brachial plexus block over 3 mins with the dose of 1.5 mg/kg (patient's weigh is 60kg, 168 cm), total:90 ml. Then, continuous infusion of Lipofundin with the dose of 0.25 ml/kg/min (150ml) over 10 mins was done. The patient was monitored during the LAR (Local Anesthesia Reversal).

85-87 mins after the LE bolus injection (220 min after the brachial plexus block),the patient could move slightly his arm.128 mins after the lipid emulsion bolus injection (261 mins after the brachial plexus block), the patient could move his hand easily.Vital signs were stable during the LAR procedure(Table 3).

Table 3

Videos:

Bolus LE. Injection: https://youtu.be/vrStLYycNrI

78 mins after LE bolus injection: https://youtu.be/SV6- FvF2dvo

93 mins after LE bolus injection: https://youtu.be/ i4oCviFJdIA

97 mins after LE bolus injection: https://youtu.be/ C1DTrW2fZo4

101 mins after LE bolus injection: https://youtu.be/ f6dr2sahf9I

104 mins after LE bolus injection: https://youtu.be/ vVnJbNlSOkY

Discussion

Lipofundin

• Composition 1000 ml emulsion contain:

• Lipofundin® MCT/LCT 20%

• Soybean oil: 100.0 g

• Medium Chain Triglycerides: 100.0 g

• Linoleic acid: 48-58 g/L

• a-Linoleic acid: 5-11 g/L

• Glycerol: 25.0 g

• Egg yolk phospholipids*: 12.0 g

• Sodium Oleate, α-Tocopherol*, Water for injections

• Megajoules/l (approx.): 7.99 (1908 kcal)

• Milliosmols/l (approx.):380

• pH:6.5-8.5

Lipid emulsions have been used to treat various drug toxicities and for total parenteral nutrition therapy. Their usefulness has also been confirmed in patients with local anesthetic-induced cardiac toxicity. The purpose of this study was to measure the hemodynamic and composition effects of lipid emulsions and to elucidate the mechanism associated with changes in intracellular calcium levels in myocardiocytes[1].

We measured hemodynamic effects using a digital analysis system after Intralipid® and Lipofundin® MCT/ LCT were infused into hearts hanging in a Langendorff perfusion system[1]. We measured the effects of the lipid emulsions on intracellular calcium levels in H9c2 cells by confocal microscopy.

Infusion of Lipofundin® MCT/LCT 20% (1 ml/kg) resulted in a significant increase in left ventricular systolic pressure compared to that after infusing modified Krebs- Henseleit solution (1 ml/kg) (P=0.003, 95% confidence interval [CI], 2.4-12.5). Lipofundin® MCT/LCT 20% had a more positive inotropic effect than that of Intralipid® 20% (P=0.009, 95% CI, 1.4-11.6). Both lipid emulsion treatments increased intracellular calcium levels. Lipofundin® MCT/ LCT (0.01%) increased intracellular calcium level more than that of 0.01% Intralipid® (P<0.05, 95% CI, 0.0-1.9).

These two lipid emulsions had different inotropic effects depending on their triglyceride component. The inotropic effect of lipid emulsions could be related with intracellular calcium level[1].

Free fatty acid (FFA) oxidation is depressed in the post ischaemic stunned myocardium and recovers in parallel with the normalization of contractile performance. Assuming a causal role for this metabolic disturbance in the pathogenesis of stunning, we questioned whether exogenous administration of high dose triglycerides during reperfusion of post ischaemic myocardium, could improve its functional recovery[2].

Thirteen dogs were chronically instrumented to measure global and regional haemodynamics and to produce a 10 min episode of regional myocardial ischaemia. In 7 dogs, Intralipid 20% was administered i.v. during the reperfusion phase. Contractile recovery of stunned myocardium was compared with control saline treatments. The series were repeated in another 6 animals, but oxfenicine (CPT I inhibitor) preceded Intralipid during reperfusion.

Contractile recovery of stunned myocardium was faster and more extensive when Intralipid was administered during reperfusion than with saline treatment (wall thickening fraction 86 +/- 6% of pre-ischaemic controls versus 52 +/- 11% at 90 min post-reperfusion; P<0.05). Oxfenicine pretreatment completely abolished this beneficial effect.

Exogenous administration of triglycerides during reperfusion of post ischaemic myocardium improves functional recovery from stunning. This beneficial effect most likely operates through enhanced FFA availability and/or oxidation since it could be abolished by selective inhibition of the carnitine palmitoyl I enzyme[2].

The authors sought to confirm a chance observation that intravenous lipid treatment increases the dose of bupivacaine required to produce asystole in rats. The authors also measured the partitioning of bupivacaine between the lipid and aqueous phases of a plasma-lipid emulsion mixture[3].

Anesthetized Sprague-Dawley rats were used in pretreatment (protocol 1) and resuscitation (protocol 2) experiments. In protocol 1, animals were pretreated with saline or 10%, 20%, or 30% Intralipid (n=6 for all groups), then received 0.75% bupivacaine hydrochloride at a rate of 10 mlx kg x min(-1) to asystole. In protocol 2, mortality was compared over a range of bolus doses of bupivacaine after resuscitation with either saline or 30% Intralipid (n=6 for all groups). The lipid:aqueous partitioning of bupivacaine in a mixture of plasma and Intralipid was measured using radiolabelled bupivacaine.

Median doses of bupivacaine (in milligrams per kilogram) producing asystole in protocol 1 were for 17.7 for saline, 27.6 for 10% Intralipid, 49.7 for 20% Intralipid, and 82.0 for 30% Intralipid (P<0.001 for differences between all groups). Differences in mean +/- SE concentrations of bupivacaine in plasma (in micrograms per millilitre) were significant (P<0.05) for the difference between saline (93.3 +/- 7.6) and 30% Intralipid (212 +/- 45). In protocol 2, lipid infusion increased the dose of bupivacaine required to cause death in 50% of animals by 48%, from 12.5 to 18.5 mg/kg. The mean lipid:aqueous ratio of concentrations of bupivacaine in a plasma-Intralipid mixture was 11.9 +/- 1.77 (n=3).

Lipid infusion shifts the dose-response to bupivacaineinduced asystole in rats. Partitioning of bupivacaine into the newly created lipid phase may partially explain this effect. These results suggest a potential application for lipid infusion in treating cardiotoxicity resulting from bupivacaine[3].

Local anesthesia drug inhibition of mitochondrial ATPase

The concentrations of n-butanol and tetracaine required for 50% inhibition of the ATPase activity of F1 particles isolated from bovine heart mitochondria were 160 mM and 1.1 mM, respectively. The results are offered as evidence that the physiological effects of these anesthetics may be due to direct interaction with membrane proteins rather than with the lipids[4].

Local anesthetics and alcohols were found to inhibit mitochondrial electron transport at several points along the chain. The anesthetics employed were the tertiary amines procaine, tetracaine, dibucaine, and chlorpromazine, and the alcohols were n-butanol, n-pentanol, n-hexanol, and benzyl alcohol. Uncoupled sonic sub mitochondrial particles from beef heart and rat liver were studied. We [5]report the following: (1) All of the anesthetics were found to inhibit each of the segments of the electron transport chain assayed; these included cytochrome c oxidase, durohydroquinone oxidase, succinate oxidase, NADH oxidase, succinate dehydrogenase, succinate-cytochrome c oxidoreductase, and NADH-cytochrome c oxidoreductase. (2) NADH oxidase and NADH-cytochrome c oxidoreductase required the lowest concentration of anesthetic for inhibition, and cytochrome c oxidase required the highest concentrations. (3) We conclude that there are several points along the chain at which inhibition occurs, the most sensitive being in the region of Complex I (NADH dehydrogenase). (4) Beef heart sub mitochondrial particles are less sensitive to inhibition than are rat liver particles. (5) Low concentrations of several of the anesthetics gave enhancement of electron transport activity, whereas higher concentrations of the same agents caused inhibition. (6) The concentrations of anesthetics (alcohol and tertiary amine) which gave 50% inhibition of NADH oxidase were lower than the reported concentrations required for blockage of frog sciatic nerve[5].

The following characteristics are reported for mitochondrial ATPase prepared by the chloroform extraction method: (1) The pH optimum for enzyme activity is at 8.0. (2) The neutral anesthetic benzocaine inhibits the enzyme at all pH values. (3) Reciprocal plots of 1/v versus 1/[ATP] show that inhibition by lidocaine, tetracaine, dibucaine, and chlorpromazine is non-competitive; slope and intercept replot are hyperbolic, showing that the inhibition is partial rather than complete[6].

Supra clavicular brachial plexus anesthesia duration

To compare the efficacy of ropivacaine 7.5 mg x ml(-1) with bupivacaine 5.0 mg x ml(-1) for subclavian perivascular brachial plexus block.

After informed consent, 104 ASA I-III adults participated in a randomized, double-blind, multi-center trial to receive 30 ml of either ropivacaine 7.5 mg x ml(-1) or bupivacaine 5.0 mg x ml(-1) for subclavian perivascular brachial plexus block prior to upper limb surgery. Onset and duration of sensory and motor block in the distribution of the axillary, median, musculo-cutaneous, radial and ulnar nerves were assessed.

Onset times and duration of sensory and motor block were similar between groups. Mean duration of analgesia for the five nerves was between 11.3 and 14.3 hr with ropivacaine and between 10.3 and 17.1 hr with bupivacaine. Quality of muscle relaxation judged as excellent by the investigators was not significantly different (ropivacaine-35/49, bupivacaine-30/49). The median time to first request for analgesia was comparable between the two groups (11- 12hr). One patient developed a grand mal seizure shortly after receiving bupivacaine and recovered consciousness within 30 min. There were no serious adverse events in the ropivacaine group.

Thirty ml ropivacaine 7.5 mg x ml(-1) (225 mg) produced effective and well tolerated brachial plexus block of long duration by the subclavian perivascular route. In this study, the results were similar to those of 30 ml bupivacaine 5.0 mg x ml(-1) [7].

We examined the outcomes and levels of patient satisfaction in 202 consecutive cases of ultrasound-guided supraclavicular brachial plexus block (SBPB) in upper limb surgery performed between September 2007 and March 2010[8]. All blocks were performed by orthopaedic surgeons using ultrasound visualisation with a high-frequency linear probe. The probe was placed in the coronal-oblique plane in the supraclavicular fossa, and the puncture was 'in-plane' from lateral to medial. Most of the blocks were performed with 0.75% ropivacaine/1% lidocaine (1:1), with or without adrenaline in 1:200,000 dilution. In 201 patients (99.5%) the brachial plexus block permitted surgery without conversion to general anaesthesia. The mean procedure time for block was 3.9 min (2 to 12), the mean waiting time for surgery was 34.1 min (10 to 64), the mean surgical time was 75.2 min (6 to 232), and the mean duration of post-anaesthetic analgesia was 437 min (171 to 992). A total of 20 patients (10%) developed a transient Horner's syndrome. No nerve injury, pneumothorax, arterial puncture or systemic anaesthetic toxicity were recorded. Most patients (96.7%) were satisfied with ultrasound-guided SBPB. This study demonstrates the efficacy and safety of ultrasound-guided SBPB for orthopaedic surgery on the upper limb[8].

Localanesthesiareversal (LAR)

Local anesthesia reversal (LAR) is a new idea based on the history of Local Anesthetic Systemic Toxicity(LAST). If Intralipid and other specific Lipid emulsions can reverse the cardiac toxicity, why it cannot reverse other features connected to the local anesthesia toxicity?It is a very logicalidea. The illogical issue is why it took almost 20 years from the first article on Intralipid and bupivacaine to invent it ?...

In our 3 cases the first patient "after finishing the lipofundin bolus injection after 4 mins (137 min after the brachial plexus block), she could move slightly her right finger.The patient could move her hand at 34 mins after the lipofundin bolus injection (166 mins after the brachial plexus block), and she could move her forearm 102 mins after the lipofundin bolus injection".

In the 2nd case"after 80-84 mins of the LE bolus injection (180 min after the brachial plexus block)the patient could move slightly his left thumb.After 184 mins since the lipid emulsion bolus injection (290 mins after the brachial block) the patient could move his hand and arm easily".

In the 3rd case "85-87 mins after the LE bolus injection (220 min after the brachial plexus block), the patient could move slightly his arm.128 mins after the lipid emulsion bolus injection (261 mins after the brachial plexus block), the patient could move his hand easily".

In all the 3 cases the reversal of the sensory and motor blocks were much faster than in the non-LAR cases as described in the medical literature. In that regards the LAR by Intralipid, Lipofundin and other similar lipid emulsions is a new method for postoperative care of patients after brachial plexus block.

Conclusion

Local anesthesia reversal (LAR) is a new idea based on the history of Local Anesthetic Systemic Toxicity(LAST). If Intralipid and other specific Lipid emulsions can reverse the cardiac toxicity, why it cannot reverse other features connected to the local anesthesia toxicity?It is a very logical idea. The illogical issue is why it took almost 20 years from the first article on Intralipid and bupivacaine to invent it?.

References

1. Park J, Kim YA, Han JY, Jin S, Ok SH, et al. (2016) Lipofundin® MCT/LCT 20% increase left ventricular systolic pressure in an ex vivo rat heart model via increase of intracellular calcium level. Korean J Anesthesiol 69: 57-62.  [ Ref ]

2. Van de Velde M, Wouters PF, Rolf N, Van Aken H, Flameng W, et al. (1996) Long-chain triglycerides improve recovery from myocardial stunning in conscious dogs. Cardiovasc Res32:1008-1015. [ Ref ]

3. Weinberg GL, VadeBoncouer T, Ramaraju GA, Garcia-Amaro MF, Cwik MJ (1998) Pretreatment or resuscitation with a lipid infusion shifts the dose-response to bupivacaine-induced asystole in rats. Anesthesiology88:1071-1075.  [ Ref ]

4. Vanderkooi G, Shaw J, Storms C, Vennerstrom R, Chignell D (1981) On the mechanism of action of anesthetics. Direct inhibition of mitochondrial F1-ATPase by n-butanol and tetracaine. BiochimBiophys Acta635:200- 203.  [ Ref ]

5. Chazotte B, Vanderkooi G (1981) Multiple sites of inhibition of mitochondrial electron transport by local anesthetics. BiochimBiophys Acta636:153-161.  [ Ref ]

6. Adade AB, Chignell D, Vanderkooi G (1984) Local anesthetics: a new class of partial inhibitors of mitochondrial ATPase. J BioenergBiomembr16:353-363. [ Ref ]

7. Vaghadia H, Chan V, Ganapathy S, Lui A, McKenna J, et al. (1999) A multicentre trial of ropivacaine 7.5 mg x ml(-1) vs bupivacaine 5 mg x ml(-1) for supra clavicular brachial plexus anesthesia. Can J Anaesth46:946-951. [ Ref ]

8. Gamo K, Kuriyama K, Higuchi H, Uesugi A, Nakase T, et al. (2014) Ultrasound-guided supraclavicular brachial plexus block in upper limb surgery: outcomes and patient satisfaction. Bone Joint J96:795-799.  [ Ref ]

### Local Anesthesia Reversal (LAR) of Total Spinal Anesthesia (TSA) by Lipofundin (Lipid Emulsion)

_List of Author(s): Joseph Eldor, Vi Pham, Tam Phuoc Tran, Xuan Loc Nguyen, Nguyen Trung Kien, Tuan Anh NGUYEN._

Abstract

These 3 case reports are the first reports in the medical literature regarding the Local Anesthesia Reversal (LAR) of Total Spinal Anesthesia (TSA) by Lipofundin which is similar to Intralipid having soybean oil fatty acids including Linoleic acid.

Keywords:

Local anesthesia reversal (LAR), Total spinal anesthesia (TSA), Lipofundin; Intralipid; Linoleic acid.

Case Report 1

A 22 years old, 158 cm of height, 40 kg weight, female, was under Spinal Anesthesia for tibia reconstruction on the right leg. Past medical history was normal. The patient had a right tibia fracture, scheduled for tibia fixation.

Spinal Anesthesia (SA) was performed at L3-4, with Bupivacaine 0.5% hyperbaric. No sedation was given. Baseline BP 126/83 mmHg, HR 90, SpO2 100% (nasal oxygenation 3l/min). SA technique was uneventful and skin incision initiated.

Approximately 5 mins after SA, patient experienced nausea, BP decreased to 90/50, HR 90. The patient got acceleration of 500 ml Crystalloid I.V. 10 min after SA, the patient's consciousness was confused, nausea, (Ramsay Score 1), BP 110/80 mmHg, HR 88, SpO2 98%. 20 Min after SA, patient was in a total coma state (Ramsay Score 6), iris was bilaterally small, BP 89/77, SpO2 98%.

(However, while asking and receiving the permission of the patient to include her videos in the article including her face (a signed permission) that was done a few days later, the patient told us that "In fact she was in the "locking syndrome" in which she heard, understood everything that was happening, but could not open her eyes nor talk (as the situation under muscle relaxant without enough sedative in general anesthesia). After the first bolus of Lipofundin she was awake nearly completely, but after that returned to the previous situation. After the second bolus, she felt much better and could respond to open her eyes as described in the report".)

The anesthesiologist decided to give 250 ml of Lipofundin 20%. After 60 ml bolus dose, the patient opened her eyes to demand (Ramsay Score 3), but felt tired, nausea, difficult to breath, otherwise hemodynamically was stable (BP 103/74, HR 88, SpO2 98%), Pinprick test lost at neck and upper extremities (C4-5).

Another 60 ml bolus of Lipofundin 20% was added. The patient opened her eyes spontaneously (Ramsay Score 2) for a while, then stayed at Ramsay score 4. Other vital signs were stable: BP 120/77, HR 76, Spontaneous breathing with SpO2 98%. The rest of Lipofundin 20% I.V continued over 30 min. During the incident, surgery was continued and lasted for 50 mins.

At the end of surgery, the Ramsay Score was 3, short of breath decreased, the pinprick test lost at T4-5, vital signs were stable (BP 120/81, HR 78, SpO2 98%) without any vasoconstricting drugs nor respiratory supports (video clip 1).

Video clip 1: https://youtu.be/JmYXsaxInak

At the recovery room, the patient received a second infusion of 250 ml vial of Lipofundin 20% over 60 mins.

At 10 min: Ramsay Score 3, Pinprick test lost at T6, Bromage Score 0, slight myoclonus on upper extremities noted, vital signs were stable (video clip 2).

Video clip 2: https://youtu.be/Jibckg-tpro

At 30 min: Ramsay Score 2, pinprick test lost at T6, Bromage Score 1. (video clip 3).

Video clip 3: https://youtu.be/UuKq5lvWVag

At 60 min: Ramsay Score 2, pinprick test lost at T7-8, Bromage Score 1- 2. (video clip 4).

Video clip 4: https://youtu.be/bQS8l1zsNUY

At 120 min: Ramsay Score 1, pinprick test lost at T 12, Bromage Score 1, no notion of any sign of myoclonus (Figure 1).

Figure 1: RAMSAY Score

Case report 2

A 28 years old, 155 cm height, 62 kg weight, healthy parturient with healthy pregnancy was scheduled for Cesarean Section for her second baby. Her previous Cesarean Section was done under Spinal anesthesia 5 years ago and was uneventfully. The laboratory tests were in normal ranges. Spinal Anesthesia was performed at L3-4 in the sitting position using Bupivacaine 10mg+Fentanyl 25 mcg+Morphine 150 mcg.

Two mins after the SA, BP decreased to 70/40, HR 120, shortness of breath, pale, SpO2 87-90%, (under oxygenation of 5L/min), the voice was lost.

She was given oxygen via mask 10L/min, 30 mg Ephedrine to recover BP, but still experienced shortness of breath and lost voice. The anesthesiologist considered these signs as LAST (Local Anesthetic Systemic Toxicity) and decided to treat the patient by LE 20% (Lipofundin 20%). After a bolus of 100 mL, the skin's color improved, SpO2 improved to 100%, BP was stable.

Twenty mins after the Infusion of 250 ml Lipofundin 20%, she regained the voice, no shortness of breath any more, SpO2 100%, BP stable.

The surgery was continued uneventfully for 30 mins. The Apgar score of the newborn was ok.

Case report 3

A 28 years old, 165 cm, 70 kg weight, first pregnancy, healthy, full-term parturient was indicated for a Cesarean Section because the fetal head did not descend.

The first Spinal Anesthesia (SA) was performed in the sitting position at L2-3 with a dose of 8 mg Bupivacaine 0.5 % heavy+50 mcg Fentanyl.

The first SA failed, so she was given another SA in the sitting position in the same level with a dose of 6 mg Bupivacaine 0.5 % heavy.

She was kept in head up position thereafter. Just after lying down on the table, she developed pale, severe dyspnea, BP decreased to 60/30, HR 50, SpO2<80%, sensory touch was lost at the upper extremities. The 500 ml Crystalloid infused rapidly, facial mask ventilation with Oxygen, and 30 mg Ephedrine given I.V to maintain BP (80/60 mmHg). Meanwhile the surgery initiated immediately to take out the neonate.

At this time the anesthesiologist was considering intubation, but he decided to use lipid emulsion therapy because he thought that it was LAST (Local Anesthetic Systemic Toxicity) and not a benign hypotension due to SA.

Since of LE 20% (Lipofundin 20%) was unavailable, the anesthesiologist used Lipofundin 10% instead.

After a rapid IV of 250ml of Lipofundin 10% (approximately 10 min), the parturient improved completely: full consciousness, normal spontaneous breathing, SpO2 100% with an oxygen face mask, stable BP, HR without using any vasoconstrictor, the sensory loss estimated at T4. At the end of the surgery (approx. 30 mins) the parturient returned to nearly normal state.

Discussion
Introduction

When a local anesthetic is injected multiple times into the subarachnoid space, it can lead to an extensive block, termed total spinal anesthesia (TSA). The most common cause is an accidental dural injection during an epidural anesthesia [1].

High neuraxial block is a common cause of anesthesiarelated maternal death. Two-thirds of high blocks were caused by accidental intrathecal injection through a presumed epidural catheter [2].

Typical features of TSA include fall in blood pressure, cessation of respiration, loss of consciousness and even cardiac arrest, which can occur within minutes of injecting a spinal drug [3]. Sometimes symptoms are atypical and difficult to identify [4].

The duration and severity of TSA is related to the type and dose of local anesthetic; for example, 0.75% bupivacaine was shown to have a mean duration of action of 1.5 h~3 h [5].

The study was part of the Thai Anesthesia Incidents Study (THAI Study) of anesthetic adverse outcomes. Study complications after spinal anesthesia [6].

During the 12-month period (March 1, 2003 - February 28, 2004), a prospective multi centered descriptive study was conducted in 20 hospitals comprised of seven university, five tertiary, four general and four district hospitals across Thailand. Anesthesia personnel filled up patient-related, surgical-related, and anesthesia-related variables and adverse outcomes of all consecutive patients receiving anesthesia on a structured data entry form. The data were collected during pre-anesthetic, intra-operative, and 24 hr post-operative period. Adverse event specific forms were used to record when these incidents occurred. Data were reviewed by three independent reviewers and analyzed to identify contributing factors by consensus.

This was registry of 40,271 spinal anesthetics from 172,697 anesthetics. The incidence of total spinal anesthesia, neurological complications, suspected myocardial ischemia, or infarction and oxygen desaturation per 10,000 spinal anesthetics were 3.48 (95% CI 1.66-5.30), 1.49 (95% CI 0.30- 2.68), 2.73 (95% CI 1.12-4.35), 0.99 (95% CI 0.39-2.56), and 6.46 (95% CI 3.98-8.94) respectively. This was not different to the incidence in other countries. Risk factors of oxygen desaturation were shorter in height [OR 0.95 (95% CI 0.92-0.97); p < 0.0011, higher ASA physical status [OR 3.37 (95% CI 1.98-5.72); p<0.001] and use of propofol [OR 5.22 (95% CI 1.78-15.35); p=0.003]. Other complications such as seizure, anaphylactic or anaphylactoid reaction, drug error, and pulmonary aspiration were scarce. There was no case of mismatched blood transfusion in the present study.

Incidence of total spinal block, neurological complication, and suspected myocardial ischemia or infarction was uncommon. Risk factors of oxygen destruction were shorter in height, higher ASA physical status, and use of propofol. Some events were considered avoidable and preventable [6].

Effect of TSA on the Heart and Peripheral Blood Flow

We evaluated the effect of total spinal anesthesia (TSA) on the heart rate and peripheral blood flow variations to evaluate if TSA could influence these parameters as indicators of autonomic nervous function (ANF) [7]. Four patients with intractable pain were treated by TSA by administration of local anesthetics (lidocaine or mepivacaine) into the C7- Th1 vertebral interspace. Power spectrum of heart rate before TSA showed three peaks; low (LO-FR, 0.04-0.095 Hz), mid (MID-FR, 0.095-0.15Hz) and high frequency areas (HI-FR, 0.15-0.3Hz). Spectral peaks of LO-FR and MID-FR disappeared during TSA (P less than 0.001). HI-FR area decreased to 3.3% of the control level (P less than 0.001). Mean peripheral blood flow was changed to 59.9% of the control level (not significant). However, peripheral blood flow variations of LO-FR decreased to 11.3% of the control level (P less than 0.001) after TSA. Furthermore, the vagal discharge disappeared promptly after TSA in dog. These results suggest that TSA depresses the vagal activity as well as the sympathetic activity innervating the cardiovascular system and therefore, heart rate and peripheral blood flow variations are totally eliminated. Thus, we conclude that heart rate and peripheral blood flow variations can serve as valid markers of ANF activity [7].

To test whether acute denervation alters the vascular effects of dopamine and dobutamine, we anesthetized 16 greyhounds and placed them on total cardiopulmonary bypass (CPB) [8]. Eight dogs received total spinal anesthesia before drug testing; eight dogs were tested in the absence of total spinal anesthesia. During dopamine and dobutamine infusions, venous capacitance [determined by the volume of the CPB venous reservoir (VR)] and mean arterial pressure (MAP) were monitored. The CPB pump flows remained constant throughout our studies. Every dog received six increasing doses of both drugs. In the absence of total spinal anesthesia, both dopamine and dobutamine increased VR (decreased venous capacitance) in a dosedependent manner. Dobutamine decreased MAP in a doserelated fashion but dopamine had no significant effect on MAP. After total spinal anesthesia, both dopamine and dobutamine produced greater dose-related increases in VR (i.e., decreases in venous capacitance) than in the absence of spinal anesthesia. Dopamine increased MAP but dobutamine had no significant effect. These data demonstrate how dopamine and dobutamine differ in their effects on the arterial circulation in the presence or absence of spinal anesthesia. The acute denervation of spinal anesthesia altered venous and arterial dose-response relationships of both drugs. Finally, our study demonstrates the effectiveness of dobutamine and, perhaps even more so, dopamine as possible alternatives to ephedrine for the pharmacologic correction of the noncardiac circulatory sequelae of spinal anesthesia [8].

TSA History

Evans described in 1928 the possible complications of spinal anesthesia [9]. Concerning respiratory paralysis, he wrote:" If respiration should cease, keep cool. Raise the lower jaw, pull the tongue forward and begin artificial respiration at a uniform rate. Mouth to mouth insufflation is the most convenient and efficacious method of artificial respiration". Twenty years before, in September 1908, before the Congress of the International Society of Surgery, in Brussels, Thomas Jonnesco from Bucharest, described his new method of general spinal anesthesia and reported 14 cases operated upon by his method [10]. Bier, who 10 years ago established the first human surgical spinal anesthesia, rejected it [10]. In a later paper in 1910 Jonnesco wrote: "It is an error to confuse lumbar rachianesthesia, conceived by Corning and popularized by Bier, with my method. As I have many times emphasized, my method is a new one and altogether distinctive, because I have generalized spinal anaesthesia, adopting it to all operations on any part of the body" [11]. Patients given high spinal anesthesia frequently either lapse into what appears to be normal sleep or may actually lose consciousness [12-15]. If patients with high spinal anesthesia are given an inhalational anesthetic such as nitrous oxide-oxygen, very low concentrations of anesthetic gases are required to maintain unconsciousness [16]. Reduction in the strength of nociceptive input may contribute to loss of consciousness by diminishing the strength of arousing stimuli arriving at cortical structures [17]. Studies with C14 labeled lidocaine in dogs have shown that the foramen magnum is not a physiological barrier, for autoradiographs and tissue samples reveal the presence of radioactivity in intracranial parts of the CNS after a relatively modest epidural dose [18]. Total spinal anesthesia has been used as a method of general anesthesia for abdominal surgery [19] and for the treatment of intractable pain [20]. Gillies and Morgan described a patient in whom a total spinal anesthesia resulted after 18 ml of inadvertent subarachnoid injection of 0.5% bupivacaine [21]. Spontaneous respiration was noted 120 minutes later, and consciousness regained after further 65 minutes. Return of respiration after 17 ml 1.5% lignocaine which resulted in total spinal analgesia occurred after 45 minutes and consciousness after further 80 minutes [22]. Four patients with intractable pain were treated by total spinal anesthesia. Power spectral analysis of heart rate and peripheral blood flow variations were studied. Vagal activity was depressed as well as the sympathetic activity innervating the cardiovascular system, so the heart rate and peripheral blood flow variations were totally eliminated [23]. Total spinal block can be elicited even after an epidural test dose like the 36-year-old parturient of Palkar et al. who developed hypotension and extensive sensory and motor block including respiratory paralysis and aphonia after injection via the epidural catheter of 3 ml lidocaine 1.5% (45 mg) with 1:200,000 epinephrine (15 microgram) [24]. The patient remained fully conscious and alert and spontaneous respiration recommenced in five minutes. Three patients were studied to determine the changes in regional skin temperature and blood flow during extensive sympathetic blockade following total spinal anesthesia. The temperature of the truncal area, arm and leg decreased by 1-degree C, whereas the temperature of the hand and foot increased by 3 degrees C [25]. Total spinal block was induced by 2% lidocaine in adult mongrel dogs. Heart rate, mean arterial pressure, cardiac index and left ventricle dp/dt max decreased significantly [26]. Ephedrine 0.5 mg/Kg elevated HR, MAP, LV dp/dt max and SVR [27]. Total spinal anesthesia blocks the vagus as well as the sympathetic nervous system and decreases heart rate variation, suggesting that neural control of the heart via the autonomic nervous system is abolished after total spinal anesthesia [25]. Matsuki et al. described a patient with primary aldosteronism who was anesthetized by total spinal anesthesia using an epidural catheter inserted at L3-4 into the subarachnoid space [28].

The trachea was intubated after intravenous injection of thiopentone 250 mg and suxamethonium 40 mg, and oxygen 3 liters/minute and nitrous oxide 2 liters/minute inhaled.

The intraoperative course was smooth and intraoperative muscle relaxation excellent. Adrenaline, noradrenaline and dopamine in the plasma remained within normal ranges. Mets et al. described a case of an unplanned version of CSEGA (Combined Spinal Epidural General Anesthesia):A 24-year-old parturient received an epidural analgesia during labor [29]. Then she was scheduled for cesarean section for failure to progress. A total dose of 30 ml 0.5% bupivacaine was administered incrementally via the epidural catheter which resulted in a patchy block that was inadequate for surgery. Twenty minutes after the last injection of epidural local anesthetic a spinal anesthesia was done which resulted in a high block that necessitated tracheal intubation and ventilation. Controlled ventilation maintained with 50% N2O and 0.5% isoflurane in oxygen until delivery of the baby after which the isoflurane was stopped and 70% N2O in oxygen was administered. No further muscle relaxation was required for the remainder of the operation which lasted 45 minutes. The patient was extubated at the end of the operation uneventfully.

CSF Lavage

High or total spinal anesthesia commonly results from accidental placement of an epidural catheter in the intrathecal space with subsequent injection of excessive volumes of local anesthetic. Cerebrospinal lavage has been shown to be effective at reversing the effects of high/total spinal anesthesia but is rarely considered in obstetric cases. Here, we describe the use of cerebrospinal lavage to prevent potential complications from high/total spinal anesthesia after unintentional placement of an intrathecal catheter in a labouring obstetric patient [30].

A 34-yr-old female presented to the labour and delivery unit in active labour. Epidural anesthesia was initiated, and after the first bolus dose, the patient experienced lower extremity motor block and shortness of breath. A high spinal was confirmed, and cerebrospinal lavage was performed. In total, 40 mL of cerebrospinal fluid (CSF) were exchanged for an equal volume of normal saline. The patient's breathing difficulties and motor block resolved quickly, and a new epidural catheter was placed after removal of the spinal catheter. Pain control was effective, and the patient delivered a healthy baby.

We show that exchange of CSF for normal saline can be used successfully to manage a high spinal in an obstetric patient. Our results suggest that CSF lavage could potentially be an important and helpful adjunct to the conventional supportive management of obstetric patients in the event of inadvertent high or total spinal anesthesia [30].

High spinal block carries significant morbidity and mortality risk. The predisposing factors are modifiable to reduce the incidence but unintentional high block secondary to migrated epidural catheter is still a possibility.

Our patient had received a combined spinal epidural anesthetic for surgery in the lithotomy position with 15 mg of 0.5% hyperbaric bupivacaine deposited intrathecally and repeated hourly boluses of 8 ml/hour of isobaric bupivacaine throughout surgery. The position of epidural catheter was confirmed with a test dose of 3ml 2% preservative free lignocaine before the first epidural injection. The last epidural medication was 0.25% bupivacaine 6ml given at the time of skin closure.

Subsequent to this injection, the patient started complaining of heaviness of breath in a low-pitched voice. His vital signs were stable (HR 92 bpm; BP 110/56 mmHg) prior to this episode. Blood pressure decreased to 85/56 mm Hg with a HR of 78 bpm. A colloid 6% HES infusion was started. The possibility of a pulmonary embolism or cranial migration of epidural drug in lithotomy position was considered. The patient could support his airway and low volume tidal breathing was observed clinically. Ventilation was gently assisted with BMV with 100% O2. The epidural catheter showed CSF on aspiration.

The technique of CSF lavage to reverse the high spinal anesthesia was employed. Slowly, CSF was removed in aliquots of 10 ml each time and replaced with 10 ml of isotonic saline. This procedure was repeated for 5 times following strict asepsis and keeping a careful watch on the patient's haemodynamics. Prompt improvements in single breath count from 4 to 12, hand grip and end tidal capnogram of spontaneous breathing was noticed. The sensory level of analgesia regressed from T2 toT4 over 15 mins and T10 by 25 mins. He was administered iv paracetamol 1 gm and tramadol 50 mg to combat pain, which was his next complaint half an hour after CSF lavage. The spinally migrated epidural catheter was removed in lateral position and patient was monitored for next 72 hours for meningeal signs, respiratory or cardiovascular deterioration and post dural puncture headache [31].

TSA due to Intercostal Nerve Block and Interscalene Nerve Block and Cervical Epidural Block

Intercostal nerve block is a recognized way of providing analgesia at thoracotomy. There is a rare association between intercostal nerve block and the complication of total spinal anesthesia. This may arise inadvertently by injection into a dural cuff extending outside the intervertebral foramen. We report our experience with a patient who sustained this life-threatening complication [32]. The patient required postoperative ventilation until the neurologic deficits resolved. The operator must be aware that intercostal nerve block runs the rare but potentially fatal risk of total spinal block [32].

We report a catastrophic postoperative complication of a prolonged interscalene block performed under general anaesthesia [33]. The course of the anaesthetic was uneventful, and the patient remained stable during his stay in the recovery area with the operative extremity paralysed and insensate. No further local anaesthetic was administered until later that day when the patient received 10 ml bupivacaine 0.25% through the catheter. Upon completion of the top-up dose, no change in the patient's status was noticed. The patient was next assessed 6.5 h later when he was found dead in his bed. A post-mortem CT scan revealed the catheter to be sited intrathecally, presumably the result of dural sleeve penetration [33].

We present a case of unintentional total spinal anesthesia, which occurred during cervical epidural block [34]. A 34-year-old man with complex regional pain syndrome of the right upper arm was treated with epidural block at C7-T1 interspace. Immediately after test-dose injection of ropivacaine 1.5 ml, he complained of paraesthesia of his upper extremities. He developed difficulty talking and breathing. Subsequently he showed a complete paralysis with the loss of consciousness, respiratory arrest, and bilateral mydriasis. Mandatory ventilation was started, and endotracheal tube was placed. Eighty minutes after the injection of ropivacaine, he recovered consciousness and spontaneous respiration resumed. Checking adequate ventilation, his trachea was extubated. Neurological dysfunction was not seen thereafter. Although test-dose injection is recommended especially in high-risk patients and case of difficulty of epidural space identification, it does not fully prevent complications. For cervical epidural block, local anesthetics should either be given at small doses or not be given as long as a possibility of spinal injection is remaining [34].

TSA is not LAST

Look on the following CHECKLIST FOR TREATMENT OF LOCAL ANESTHETIC SYSTEMIC TOXICITY {LAST) :  https://www.asra.com/content/documents/asra_last_ checklist_2018.pdf

It is based on The Third American Society of Regional Anesthesia and Pain Medicine Practice Advisory on Local Anesthetic Systemic Toxicity . Executive Summary 2017. Reg Anesth Pain Med 2016; 43: 113-123.

Look on the second page under Risk Reduction (Be sensible):

\- Second point: " Local anesthetic blood levels are influenced by site of injection and dose".

\- Fourth point: "Aspirate the syringe prior to each injection while observing for blood in the syringe or tubing".

In other words: LAST refers to LA>BLOOD>ST

It has nothing to do with TSA...

Of course, the LA in the blood can have "altered mental status, neurological symptoms or signs of cardiovascular instability..."

These 3 case reports are the first reports in the medical literature regarding the Local Anesthesia Reversal (LAR) of Total Spinal Anesthesia (TSA) by Lipofundin which is similar to Intralipid having soybean oil fatty acids including Linoleic acid.

Conclusion

These 3 case reports are the first reports in the medical literature regarding the Local Anesthesia Reversal ( LAR) of Total Spinal Anesthesia (TSA) by Lipofundin.

References

1. Hodgkinson R (1981) Total spinal block after epidural injection into an interspace adjacent to an inadvertent dural perforation. Anesthesiology 55: 593-595.  [ Ref ]

2. Davies JM, Posner KL, Lee LA, Cheney FW, Domino KB (2009) Liability associated with obstetric anesthesia: a closed claims analysis. Anesthesiology 110: 131-139.  [ Ref ]

3. Gillies ID, Morgan M (1973) Accidental total spinal analgesia with bupivacaine. Anaesthesia 28: 441-445.  [ Ref ]

4. Siddik-Sayyid SM, Gellad PH, Aouad MT (2012) Total spinal block after spinal anesthesia following ongoing epidural analgesia for cesarean delivery. J Anesth 26: 312-313.  [ Ref ]

5. Wilkinson GR, Lund PC (1970) Bupivacaine levels in plasma and cerebrospinal fluid following peridural administration. Anesthesiology 33: 482-486.  [ Ref ]

6. Charuluxananan S, Thienthong S, Rungreungvanich M, Chanchayanon T, Chinachoti T, et al. (2007) The Thai Anesthesia Incidents Study (THAI study) of morbidity after spinal anesthesia: a multi-centered registry of 40,271 anesthetics. J Med Assoc Thai 90: 1150-1160.  [ Ref ]

7. Goda Y, Kimura T, Goto Y, Kemmotsu O (1989) Power spectral analysis of heart rate and peripheral blood flow variations during total spinal anesthesia. Masui 38: 1275-1281. [ Ref ]

8. Butterworth JF, Austin JC, Johnson MD, Berrizbeitia LD, Dance GR, et al. Effect of total spinal anesthesia on arterial and venous responses to dopamine and dobutamine. Anesth Analg 66: 209-214. [ Ref ]

9. Evans CH (1928) Possible complications with spinal anesthesia. Their recognition and the measures employed to prevent and to control them. Am J Surgery 5: 581-593.  [ Ref ]

10. Jonnesco T (1909) Remarks on general spinal analgesia. Br Med J 2: 1396-1401.  [ Ref ]

11. Jonnesco T (1910) Concerning general rachianesthesia. Am J Surgery 24: 33.  [ Ref ]

12. Koster H, Kasman LP (1929) Spinal anesthesia for the head, neck and thorax: its relation to respiratory paralysis. Surg Gynecol Obstet 49: 617.  [ Ref ]

13. Vehrs GR (1934) Spinal anesthesia: Technic and clinical application. St Louis: The C.V. Mosby Co.  [ Ref ]

14. Jones RGG (1953) A complication of epidural technique. Anaesthesia 8: 242.  [ Ref ]

15. Huvos MC, Greene NM, Glaser GH (1962) Electroencephalographic studies during acute subtotal denervation in man. Yale J Biol Med 34: 592. [ Ref ]

16. Greene NM (1952) Hypotensive spinal anesthesia. Surg Gynecol Obstet 95: 331.  [ Ref ]

17. Kendig JJ (1993) Spinal cord as a site of anesthetic action. Anesthesiology 79: 1161-1162. [ Ref ]

18. Bromage PR, Joyal AC, Binney JC (1963) Local anaesthetic drugs: Penetration from the spinal extradural space into the neuraxis. Science 140: 392. [ Ref ]

19. Evans TI (1974) Total spinal anaesthesia. Anaesth Intensive Care 2: 158-163.  [ Ref ]

20. Yamashiro H, Hirano K (1987) Treatment with total spinal block of severe herpetic neuralgia accompanying median and ulnar nerve palsy. Masui 36: 971-975. [ Ref ]

21. Gillies IDS, Morgan M (1973) Accidental total spinal analgesia with bupivacaine. Anaesthesia 28: 441-445.[ Ref ]

22. DeSaram M (1956) Accidental total spinal analgesia. A report of three cases. Anaesthesia 11: 77.  [ Ref ]

23. Goda Y, Kimura T, Goto Y, Kemmotsu O (1989) Power spectral analysis of heart rate and peripheral blood flow variations during total spinal anesthesia. Masui 38: 1275-1281. [ Ref ]

24. Palkar NV, Boudreaux RC, Mankad AV (1992) Accidental total spinal block: a complication of an epidural test dose. Can J Anaesth 39: 1058- 1060. [ Ref ]

25. Kimura T, Goda Y, Kemmotsu O, Shimada Y (1992) Regional differences in skin blood flow and temperature during total spinal anaesthesia. Can J Anaesth 39: 123-127. [ Ref ]

26. Kobori M, Negishi H, Masuda Y, Hosoyamada A (1991) Changes in respiratory, circulatory, endocrine, and metabolic systems under induced total spinal block. Masui 40: 1804-1809. [ Ref ]

27. Kobori M, Negishi H, Masuda Y, Hosoyamada A (1990) Changes in systemic circulation under induced total spinal block and choice of vasopressors. Masui 39: 1580-1585. [ Ref ]

28. Matsuki M, Muraoka M, Oyama T (1988) Total spinal anaesthesia for a Jehovah`s Witness with primary aldosteronism. Anaesthesia 43: 164- 165.  [ Ref ]

29. Mets B, Broccoli E, Brown AR (1993) Is spinal anesthesia after failed epidural anesthesia contraindicated for cesarean section? Anesth Analg 77: 629-631.  [ Ref ]

30. Ting HY, Tsui BC (2014) Reversal of high spinal anesthesia with cerebrospinal lavage after inadvertent intrathecal injection of local anesthetic in an obstetric patient. Can J Anaesth 61: 1004-1007. [ Ref ]

31. Ashima S, Kiran G, Padmaja D, Gopinath R (2014) CSF Lavage for high spinal- A technical miracle. BJA: British Journal of Anaesthesia 113.  [ Ref ]

32. Chaudhri BB, Macfie A, Kirk AJ (2009) Inadvertent total spinal anesthesia after intercostal nerve block placement during lung resection. Ann Thorac Surg 88: 283-284.  [ Ref ]02065-1/abstract)

33. Yanovski B, Gaitini L, Volodarski D, Ben-David B (2012) Catastrophic complication of an interscalene catheter for continuous peripheral nerve blockanalgesia. Anaesthesia 67: 1166-1169.  [ Ref ]

34. Hara K, Sata T (2006) Unintentional total spinal anesthesia during cervical epidural block with ropivacaine. Masui 55: 1168-1169. [ Ref ]

The First Case Report of Local Anesthesia Reversal (LAR) of the Upper Arm Brachial Plexus Block by Lipid Emulsion

List of Author(s): Joseph Eldor, Hien VV, Kien NT.

Abstract

A 25 years old male was diagnosed as having natural stump in left forearm due to detonator. He needed an emergency surgery for cutting damaged tissue and repair of the stump. The patient was anesthetized by Ultrasound guided brachial plexus block through the Supra Clavicular approach with Lidocaine 4 mg/kg combined with Ropivacaine 1mg/kg and Epinephrine 1/200.000 in total of 30 ml solution. Lipid emulsion (Lipofundin 20%, B. Braun) bolus injection was given 70 min after the Brachial plexus block over 2 min in a dose of 1.5 mg/kg (patient's weight is 60 kg). After 2 min of the Lipid emulsion bolus injection he could move slightly his left arm. Full Local Anesthesia Reversal (LAR) was achieved after 255 min from the Brachial plexus block performance.

It is the first case report in the medical literature of Local Anesthesia Reversal (LAR) of the upper arm Brachial plexus block by Lipid Emulsion.

Keywords:

Intralipid; Lipid emulsion; LE;Lipofundin;Ropivacaine supraclavicular block; Brachial plexus block; Local anesthesia reversal; LAR.

Case report

A 25 years old male was diagnosed as having natural stump in left forearm due to detonator.

• (Photo: http://www.csen.com/stump1.jpg)

• (X-ray: http://www.csen.com/stump2.jpg)

He needed an emergency surgery for cutting damaged tissue and repair of the stump.The operation was done on Feb 16th, 2018 at the Military Hospital 103, Vietnam Military Medical University. The patient was anesthetized by Ultrasound guided brachial plexus block through the Supra Clavicular approach with Lidocaine 4 mg/kg combined with Ropivacaine 1mg/kg and Epinephrine 1/200.000 in total of 30 ml solution.

• Onset time of Anesthesia: 5 min.

• Anesthesia effect was very good for the surgery.

• Duration of surgery: 50 min

Surgery was accomplished in 65 min after the Brachial plexus block. Sensory and motor function of the left hand that were assessed before injection were absent completely.

Lipid emulsion (Lipofundin 20%, B. Braun) bolus injection was given 70 min after the Brachial plexus block over 2 min in a dose of 1.5 mg/ kg (patient's weight is 60 kg). The patient was monitored closely in the operating room for 1 hour:

• (Video 1: https://www.youtube.com/watch?v=93QrTB- -2_o)

After 2 min of the Lipid emulsion bolus injection he could move slightly his left arm.Vital signs were stable after the Lipid emulsion bolus injection.

After 185 min from the lipid emulsion bolus injection the sensory and motor function of the left hand were fully recovered. He could move his left hand without any difficulty. It means that full Local Anesthesia Reversal (LAR) was achieved after 255 min from the Brachial plexus block performance.

• (Video 2: https://www.youtube.com/watch?v=K2H4h- GLZko&feature=youtu.be)

Discussion

Supraclavicular block

The first percutaneous supraclavicular block was performed in 1911 by German surgeon Diedrich Kulenkampff (1880–1967)[1].Kulenkampff subjected himself to the supraclavicular block. Later that year, Georg Hirschel (1875–1963) described a percutaneous approach to the brachial plexus from the axilla[2].By the late 1940s, clinical experience with brachial plexus block in both peacetime and wartime surgery was extensive, and new approaches tothis technique began to be described[3]. For example, In 1946, F. Paul Ansbro was the first to describe a continuous brachial plexus block technique. He secured a needle in the supraclavicular fossa and attached tubing connected to a syringe through which he could inject incremental doses of local anesthetic[4]. The subclavian perivascular block was first described by Winnie and Collins in 1964[5]. This approach became popular due to its lower risk of pneumothorax compared to the traditional Kulenkampffapproach. The infraclavicular approach was first developed by Raj. In 1977,Selander described a technique for continuous brachial plexus block using anintravenous catheter secured in the axilla[6].

Prolonged blockade

There are a few reports of prolonged blockade following seemingly flawlesstechnique of performing block. Complete recovery in those case reportsvaried from 40 to 84 hours after the block[7-8]. None of the papers haveclearly stated the reason behind the long blockade. Injecting the localanesthetic too close to the nerves and chronic treatment with lithium has beenproposed as reasons behind these unusually prolonged blocks. Luduenabelieved that causes of prolonged blockade are often unknown and if theduration is longer than 24 hours then probability of nerve damage should beconsidered[9].

Regular blockade

The present study compares the effectiveness of 0.25% ropivacaine and 0.25% bupivacaine in 44 patients receiving a subclavian perivascular brachial plexus block for upper extremity surgery. The patients were assigned to two equal groups in this randomized, double-blind study; one group received ropivacaine 0.25% (112.5 mg) and the other, bupivacaine 0.25% (112.5 mg), both without epinephrine. Onset times for analgesia and anesthesia in each of the C-5 through T-1 brachial plexus dermatomes did not differ significantly between the two groups. The mean onset time for analgesia ranged from 11.2 to 20.2 min, and the mean onset time for anesthesia ranged from 23.3 to 48.2 min. The onset of motor block differed only with respect to paresis in the hand, with bupivacaine demonstrating a shorter onset time than ropivacaine. The duration of sensory and motor block also was not significantly different between the two groups. The mean duration of analgesia ranged from 9.2 to 13.0 h, and the mean duration of anesthesia ranged from 5.0 to 10.2 h. Both groups required supplementation with peripheral nerve blocks or general anesthesia in a large number of cases, with 9 of the 22 patients in the bupivacaine group and 8 of the 22 patients in the ropivacaine group requiring supplementation to allow surgery to begin. In view of the frequent need for supplementation noted with both 0.25% ropivacaine and 0.25% bupivacaine, we do not recommend using the 0.25% concentrations of these local anesthetics to provide brachial plexus block [10].

The effects of clonidine and epinephrine, administered into the brachial plexus sheath, were evaluated in 60 patients who underwent surgery of the upper limb. All patients received 40 to 50 ml of 0.25% bupivacaine, injected into the brachial plexus sheath, using the supraclavicular technique. The patients were randomly allocated to two groups so that 30 patients received 150 micrograms clonidine hydrochloride (Group I), and 30 received 200 micrograms epinephrine (Group II). The quality and the duration of analgesia were assessed as well as the possible side-effects. The block produced with the addition of clonidine was longer (994.2 +/- 34.2 vs 728.3 +/- 35.8 min) and superior to that with epinephrine (P less than 0.001). No major side-effects were recorded. We conclude that the injection of clonidine into the brachial plexus sheath is an attractive alternative to epinephrine to prolong the duration of analgesia following upper limb surgery under conduction anaesthesia[11].

This studycompared the effectiveness of 0.5% ropivacaine and 0.5% bupivacaine for brachial plexus block[12]. Fortyeight patients received a subclavian perivascular brachial plexus block for upper-extremity surgery. One group (n=24) received ropivacaine 0.5% (175 mg) and a second group (n=24) received bupivacaine 0.5% (175 mg), both without epinephrine. Onset times for analgesia and anesthesia in each of the C5 through T1 brachial plexus dermatomes did not differ significantly between groups. Duration of analgesia and anesthesia was long (mean duration of analgesia, 13- 14h; mean duration of anesthesia, 9-11h) and also did not differ significantly between groups. Motor block was profound, with shoulder paralysis as well as hand paresis developing in all of the patients in both groups. Two patients in each group required supplemental blocks before surgery. Ropivacaine 0.5% and bupivacaine 0.5% appeared equally effective in providing brachial plexus anesthesia[12].

The mixture of 1% lidocaine and 0.2% tetracaine with 1:200,000 epinephrine, so-called "supercaine," has been used extensively for axillary brachial plexus blockade for several decades. Since the advent of bupivacaine, the supercaine mixture has fallen into relative disuse despite its record of effectiveness and safety. No studies have been done recently to evaluate quality of anesthesia, duration of postoperative analgesia, and degree of patient satisfaction with this mixture when used for axillary brachial plexus blockade. The assumptions were as follows: surgical anesthesia will be adequate, length of postoperative analgesia will be approximately 4 to 9 hours, and patients will be highly satisfied. The specific aim of the present study was to describe the anesthetic characteristics of supercaine. Patients between 18 and 65 years of age received a standard mixture of supercaine, totalling 450-500 mg of lidocaine and 90 to 100 mg of tetracaine. Epinephrine in a solution of 1:200,000 and an 8.4% solution of sodium bicarbonate were added, and the trans arterial technique was used. Patients were contacted on postoperative day 1 to determine the duration of sensory and motor block; overall satisfaction with the block was rated. Data were analyzed with the Statistical Program for the Social Sciences (SPSS, Chicago, Ill) and Stata (Stata Corp., College Station, Tax) computer programs. The mean +/- SD findings were as follows: duration of sensory block, 465 +/- 204 minutes; duration of motor block, 473 +/- 214 minutes; patient satisfaction score, 9 +/- 1 on a 1 to 10 scale. Data are reported within a 95% confidence interval. Variables examined and compared were not statistically significant. We concluded that the duration of block supports findings reported in the literature, patients equate duration of sensory block with duration of motor block, differences in duration were probably due to levels of provider experience, and patients were extremely satisfied with the anesthetic[13].

Ultrasound-guided supraclavicular brachial plexus block (USSB) provides excellent postoperative analgesia after upper extremity surgery. Dexamethasone and clonidine have been added to local anesthetics to enhance and prolong the duration of analgesia.

The objective of this randomized prospective study is to evaluate the efficacy of dexamethasone, clonidine, or combination of both as adjuvants to ropivacaine on the duration of USSB for postoperative analgesia.

Patients receiving USSB for postoperative pain control for upper extremity surgery were randomized to one of four groups; ropivacaine 0.5 %, ropivacaine 0.5 % with 4 mg dexamethasone, ropivacaine 0.5% with 100 mcg clonidine , or ropivacaine 0.5 % with 4 mg dexamethasone and 100 mcg clonidine. Pain scores, sensory and motor function were evaluated at post anesthesia care unit (PACU), discharge and at 24 h postoperatively.

The duration of sensory and motor blocks were significantly longer in clonidine groups when compared to ropivacaine alone [Sensorial analgesia: ropivacaine alone 13.4±6, Ropivacaine-Clonidine 17.4 ± 6; Ropivacaine- Dexamethasone-Clonidine 18.8±6.2; Motor blocks: Ropivacaine 12 ± 5, Ropivacaine-Clonidine 16.8 ± 5.2, Ropivacaine-Dexamethasone-Clonidine 18.2 ± 5.7]. In clonidine groups, there was significantly prolongation of motor and sensory block when compared to ropivacaine alone group.

The results demonstrated that clonidine significantly prolongs the duration of ropivacaine effects for the postoperative analgesia in patient underwent upper arm surgeries[14].

The duration of effect for axillary plexus block using ropivacaine is highly variable. The available literature does not offer any plausible means of predicting time of block offset for individual patients, making it difficult to give accurate information and plan postoperative analgesics. This study was designed to identify factors influencing axillary plexus block offset time.

A total of 92 patients participated in this prospective double centred observational study. All patients were scheduled for axillary plexus block with ropivacaine 0.75% and subsequent block duration was recorded.

Mean time of axillary plexus block offset was 13.5 hours, with a range of 4.8 to 25.4 hours. No statistical significant differences in offset time was seen with regard to gender, age, body weight, BMI and ASA-classification. A trend for increasing duration of blocks associated with increasing age was observed. No statistically significant difference was identified in block duration between blocks performed with nerve stimulator guidance versus ultrasound guidance. Similarly, neither dose nor volume of ropivacaine 0.75% was identified as a factor influencing block duration.

This prospective study demonstrates a large inter individual variation in time of axillary plexus block offset using ropivacaine0.75%. The lack of association between offset time and both demographic and block performance factors, makes predictability of individual duration of axillary plexus blocks in clinical practice extremely difficult. We suggest that all patients should be made aware of such variability in duration prior to block placement[15].

On a pharmacologic basis, levobupivacaine is expected to last longer than ropivacaine. However, most reports of these anesthetics for brachial plexus block do not suggest a difference in analgesic effect. The aim of this study is to compare the postoperative analgesic effects of levobupivacaine and ropivacaine when used for treating ultrasound-guided brachial plexus block.

A total of 62 patients undergoing orthopaedic surgery procedures were prospectively enrolled and randomized to receive levobupivacaine (group L, N = 31) or ropivacaine (group R, N = 31). The duration of analgesia, offset time of motor block, need for rescue analgesics, and sleep disturbance on the night of surgery were recorded. Pain score was recorded on the day of surgery, and on postoperative days 1 and 2.

There was no difference in the time interval until the first request for pain medication comparing the two groups (group L: 15.6 [11.4, 16.8] hours; group R: 12.5 [9.4, 16.0] hours, P = 0.32). There was no difference in the duration of motor block (group L: 12.2 [7.6, 14.4] hours; group R: 9.4 [7.9, 13.2] hours, P = 0.44), pain score (P = 0.92), need for rescue analgesics (group L: 55%; group R: 65%, P = 0.6), or rate of sleep disturbance (group L: 61%, group R: 58%, P = 1.0) on comparing the two groups.

There was no difference in postoperative analgesia comparing levobupivacaine and ropivacaine when used for brachial plexus block[16].

For any surgery in the upper extremity that does not involve the shoulder, a supraclavicular block is preferred, as it is a safe procedure associated with rapid onset and reliable anaesthesia. Although ropivacaine has been extensively studied for epidural anaesthesia, very few reports exist on its use in supraclavicular brachial plexus block.

This studywas conducted to investigate and compare the effectiveness of supraclavicular brachial plexus anaesthesia with two different concentrations of ropivacaine (0.5% and 0.75%) and to compare them with the standard 0.5% bupivacaine[17].

Ninety patients of age 18 to 60 years belonging to American Society of Anaesthesiologists (ASA) status 1 or 2, admitted to Pondicherry Institute of Medical Sciences were chosen for the study and were divided into three groups. Group A received 30 ml of 0.5% bupivacaine, group B received 30 ml of 0.5% ropivacaine and group C received 30 ml of 0.75% ropivacaine into the supraclavicular region, by a nerve-stimulator technique. Onset time of each of the drug was recorded both for the sensory and motor block. Duration of sensory and motor block was recorded along with peri-operative haemodynamic monitoring.

The onset of complete sensory and motor block observed with both ropivacaine groups and bupivacaine was similar (16.85±6.67 min in group A, 17.79±5.03 min in group B and 18.48±6.14 in group C, p>0.05); onset of motor block (21.45±4.45 min in group A, 22.23±4.05 min in group B and 22.33±5.17 in group C, p< 0.05). The duration of sensory block with 0.5% bupivacaine was 11.58 hours, with 0.5% ropivacaine was 9.02 hours with 0.75% ropivacaine was 8.87 hours (p<0.001). The duration of motor block with 0.5% bupivacaine was 12.94 hours, with 0.5% ropivacaine was 8.29 hours with 0.75% ropivacaine was 7.89 hours (p<0.001). Multiple comparison test with Bonferroni correction showed there was statistically significant difference in mean duration of sensory block between Group A (0.5% bupivacaine) and Group B (0.5% ropivacaine) and also between Group A (0.5% bupivacaine) and Group C (0.75% ropivacaine). However, there were no statistically significant difference in mean duration of sensory block between Group B (0.5% ropivacaine) and Group C (0.75% ropivacaine). The preoperative, intra operative and postoperative heart rate, systolic & diastolic blood pressure and oxygen saturation were comparable among the three study groups (p>0.05). No side effects were recorded in the study.

The onset of sensory and motor block was similar in all the three groups. However, when compared to bupivacaine group, recovery of motor functions was faster in both the ropivacaine groups. Patients in all the 3 groups did not experience any adverse effects[17].

Lipid Emulsion Effects on Mitochondria and Intracellular Calcium

Local anesthetic toxicity is thought to be mediated partly by inhibition of cardiac mitochondrial function. Intravenous (i.v.) lipid emulsion may overcome this energy depletion, but doses larger than currently recommended may be needed for rescue effect. In this randomized study with anesthetized pigs, we compared the effect of a large dose, 4 mL/kg, of i.v. 20% Intralipid® (n=7) with Ringer's acetate (n=6) on cardiovascular recovery after a cardiotoxic dose of bupivacaine[18]. We also examined mitochondrial respiratory function in myocardial cell homogenates analyzed promptly after needle biopsies from the animals. Bupivacaine plasma concentrations were quantified from plasma samples. Arterial blood pressure recovered faster and systemic vascular resistance rose more rapidly after Intralipid than Ringer's acetate administration (p<0.0001), but Intralipid did not increase cardiac index or left ventricular ejection fraction. The lipid-based mitochondrial respiration was stimulated by approximately 30% after Intralipid (p<0.05) but unaffected by Ringer's acetate. The mean (standard deviation) area under the concentration-time curve (AUC) of total bupivacaine was greater after Intralipid (105.2 (13.6) mg·min/L) than after Ringer's acetate (88.1 (7.1) mg·min/L) (p=0.019). After Intralipid, the AUC of the lipid-un-entrapped bupivacaine portion (97.0 (14.5) mg·min/L) was 8% lower than that of total bupivacaine (p<0.0001). To conclude, 4 mL/kg of Intralipid expedited cardiovascular recovery from bupivacaine cardiotoxicity mainly by increasing systemic vascular resistance.The increased myocardial mitochondrial respiration and bupivacaine entrapment after Intralipid did not improve cardiac function[18].

Lipid emulsions have been used to treat various drug toxicities and for total parenteral nutrition therapy. Their usefulness has also been confirmed in patients with local anesthetic-induced cardiac toxicity. The purpose of this study was to measure the hemodynamic and composition effects of lipid emulsions and to elucidate the mechanism associated with changes in intracellular calcium levels in myocardiocytes.

Wemeasured hemodynamic effects using a digital analysis system after Intralipid® and Lipofundin® MCT/ LCT were infused into hearts hanging in a Langendorff perfusion system[20]. We measured the effects of the lipid emulsions on intracellular calcium levels in H9c2 cells by confocal microscopy.

Infusion of Lipofundin® MCT/LCT 20% (1ml/kg) resulted in a significant increase in left ventricular systolic pressure compared to that after infusing modified Krebs- Henseleit solution (1ml/kg) (P=0.003, 95% confidence interval [CI], 2.4-12.5). Lipofundin® MCT/LCT 20% had a more positive inotropic effect than that of Intralipid® 20% (P=0.009, 95% CI, 1.4-11.6). Both lipid emulsion treatments increased intracellular calcium levels. Lipofundin® MCT/ LCT (0.01%) increased intracellular calcium level more than that of 0.01% Intralipid® (P<0.05, 95% CI, 0.0-1.9).

These two lipid emulsions had different inotropic effects depending on their triglyceride component. The inotropic effect of lipid emulsions could be related with intracellular calcium level[19].

Accidental intravascular or high-dose injection of local anesthetics (LA) can result in serious, potentially lifethreatening complications. Indeed, adequate supportive measures and the administration of lipid emulsions are required in such complications. The study's objectives were threefold: (i) evaluate the myocardial toxicity of levobupivacaine when administered intravenously; (ii) investigate levobupivacaine toxicity on cardiomyocytes mitochondrial functions and cellular structure; (iii) assess the protective effects of a lipid emulsion in the presence or absence of myocardial ischemia. Domestic pigs randomized into two groups of 24 animals each, with either preserved coronary circulation or experimental myocardial ischemia. Six animals from each group received either: (i) single IV injection of saline, (ii) lipid emulsion (Intralipid(®) ), (iii) levobupivacaine, (iv) combination levobupivacaine- Intralipid(®) . Serially measured endpoints included: heart rate, duration of the monophasic action potentials (dMAP), mean arterial pressure, and peak of the time derivative of left ventricular pressure (LV dP/dtmax). In addition, the following cardiomyocytes mitochondrial functions were measured: reactive oxygen species (ROS) production, oxidative phosphorylation, and calcium retention capacity (CRC) as well as the consequences of ROS production on lipids, proteins, and DNA. IV injection of levobupivacaine induced sinus bradycardia and reduced dMAP and LV dP/ dtmax.At the mitochondrial level, oxygen consumption and CRC were decreased. In contrast, ROS production was increased leading to enhanced lipid peroxidation and structural alterations of proteins and DNA. Myocardial ischemia was associated with global worsening of all changes. Intralipid(®) quickly improved haemodynamics. However, beneficial effects of Intralipid(®) were less clear after myocardial ischemia[20].

Cocaine intoxication leads to over 500,000 emergency department visits annually in the United States and ethanol cointoxication occurs in 34% of those cases. Cardiotoxicity is an ominous complication of cocaine and cocaethylene overdose for which no specific antidote exists. Because infusion of lipid emulsion (Intralipid) can treat lipophilic local anesthetic toxicity and cocaine is an amphipathic local anesthetic, the authorstested whether lipid emulsion could attenuate cocaine cardiotoxicity in vivo[21]. The effects of lipid emulsion were compared with the metabolically inert sulfobutylether-β-cyclodextrin (SBE-β-CD; Captisol) in an isolated heart model of cocaine and cocaethylene toxicity to determine if capture alone could exert similar benefit as lipid emulsion, which exhibits multimodal effects. The authors then tested if cocaine and cocaethylene, like bupivacaine, inhibit lipid-based metabolism in isolated cardiac mitochondria.

For whole animal experiments, Sprague-Dawley rats were anesthetized, instrumented, and pretreated with lipid emulsion followed by a continuous infusion of cocaine to assess time of onset of cocaine toxicity. For ex vivo experiments, rat hearts were placed onto a nonrecirculating Langendorff system perfused with Krebs-Henseleit solution. Heart rate, left ventricle maximum developed pressure (LVdevP), left ventricle diastolic pressure, maximum rate of contraction (+dP/dtmax), maximum rate of relaxation (-dP/ dtmax), rate-pressure product (RPP = heart rate×LVdevP), and line pressure were monitored continuously during the experiment. A dose response to cocaine (10, 30, 50, and 100 μmol/L) and cocaethylene (10, 30, and 50 μmol/L) was generated in the absence or presence of either 0.25% lipid emulsion or SBE-β-CD. Substrate-specific rates of oxygen consumption were measured in interfibrillar cardiac mitochondria in the presence of cocaine, cocaethylene, ecgonine, and benzoylecgonine.

Treatment with lipid emulsion delayed onset of hypotension (140 seconds vs. 279 seconds; p=0.008) and asystole (369 seconds vs. 607 seconds; p=0.02) in whole animals. Cocaine and cocaethylene induced dose-dependent decreases in RPP, +dP/dtmax, and -dP/dtmaxabs (p<0.0001) in Langendorff hearts; line pressure was increased by cocaine and cocaethylene infusion, but not altered by treatment. Lipid emulsion attenuated cocaine- and cocaethyleneinduced cardiac depression. SBE-β-CD alone evoked a mild cardiodepressant effect (p<0.0001) but attenuated further cocaine- and cocaethylene-induced decrements in cardiac contractility at high concentrations of drug (100 μmol/L; p<0.001). Finally, both cocaine and cocaethylene, but not ecgonine and benzoylecgonine, inhibited lipid-dependent mitochondrial respiration by blocking carnitine exchange (p<0.05).A commercially available lipid emulsion was able to delay progression of cocaine cardiac toxicity in vivo. Further, it improved acute cocaine- and cocaethyleneinduced cardiac toxicity in rat isolated heart while SBE-β- CD was effective only at the highest cocaine concentration. Further, both cocaine and cocaethylene inhibited lipiddependent mitochondrial respiration. Collectively, this suggests that scavenging-independent effects of lipid emulsion may contribute to reversal of acute cocaine and cocaethylene cardiotoxicity, and the beneficial effects may involve mitochondrial lipid processing[21].

We hypothesized that acute lipid-induced insulin resistance would be attenuated in high-oxidative muscle of lean trained (LT) endurance athletes due to their enhanced metabolic flexibility and mitochondrial capacity[22]. Lean sedentary (LS), obese sedentary (OS), and LT participants completed two hyperinsulinemic euglycemic clamp studies with and without (glycerol control) the coinfusion of Intralipid. Metabolic flexibility was measured by indirect calorimetry as the oxidation of fatty acids and glucose during fasted and insulin-stimulated conditions, the latter with and without lipid oversupply. Muscle biopsies were obtained for mitochondrial and insulin-signaling studies. During hyperinsulinemia without lipid, glucose infusion rate (GIR) was lowest in OS due to lower rates of nonoxidative glucose disposal (NOGD), whereas state 4 respiration was increased in all groups. Lipid infusion reduced GIR similarly in all subjects and reduced state 4 respiration. However, in LT subjects, fat oxidation was higher with lipid oversupply, and although glucose oxidation was reduced, NOGD was better preserved compared with LS and OS subjects. Mitochondrial performance was positively associated with better NOGD and insulin sensitivity in both conditions. We conclude that enhanced mitochondrial performance with exercise is related to better metabolic flexibility and insulin sensitivity in response to lipid overload[22].

Conclusion

It is the first case report in the medical literature of Local Anesthesia Reversal ( LAR) of the upper arm Brachial plexus block by Lipid Emulsion.

References

1. Kulenkampff D (1911) Zuranästhesierung des plexus brachialis On anesthesia of the brachial plexus]. Zentralblatt für Chirurgie (in German) 38: 1337-1340. [[ Ref ]

2. Hirschel G (1911) Die anästhesierung des plexus brachialis fuer die operationen an der oberenextremitat Anesthesia of the brachial plexus for operations on the upper extremity]. MunchenerMedizinischeWochenschrift (in German) 58: 1555-1556. [[ Ref ]

3. de Pablo JS, Diez-Mallo J (1948) Experience with Three Thousand Cases of Brachial Plexus Block: Its Dangers: Report of a Fatal Case. Annals of Surgery 128: 956-964. [ Ref ]

4. Ansbro FP (1946) A Method of Continuous Brachial Plexus Block. American Journal of Surgery 71: 716-722.  [ Ref ]

5. Winnie AP, Collins VJ (1964) Thesubclavian perivascular technique of brachial plexus anesthesia. Anesthesiology 25: 35-63.  [ Ref ]

6. Selander D (1977) Catheter technique in axillary plexus block: presentation of a new method. Acta AnaesthesiologicaScandinavica 21: 324-329.  [ Ref ]

7. Brockway MS, Winter AW, Wildsmith JA (1989) Prolonged brachial plexus block with 0.42% bupivacaine. Br J Anaesth 63: 604-645. [ Ref ]38715-9/abstract)

8. Lehavi A, Shenderey B, Katz YS (2012) Prolonged nerve blockade in a patient treated with lithium. Local Reg Anesth 5: 15-16.  [ Ref ]

9. Luduena FP (1969) Duration of local anesthesia. Annu Rev Pharmacol 9: 503-520.  [ Ref ]

10. Hickey R, Rowley CL, Candido KD, Hoffman J, Ramamurthy S, et al. (1992) A comparative study of 0.25% ropivacaine and 0.25% bupivacaine for brachial plexus block. AnesthAnalg 75: 602-606. [ Ref ]

11. Eledjam JJ, Deschodt J, Viel EJ, Lubrano JF, Charavel P, et al. (1991) Brachial plexus block with bupivacaine: effects of added alphaadrenergic agonists: comparison between clonidine and epinephrine. Can J Anaesth 38: 870-875. [ Ref ]

12. Hickey R, Hoffman J, Ramamurthy S (1991) A comparison of ropivacaine 0.5% and bupivacaine 0.5% for brachial plexus block. Anesthesiology 74: 639-642. [ Ref ]

13. Berry JS, Heindel L (1999) Evaluation of lidocaine and tetracaine mixture in axillary brachial plexus block. AANA J 67: 329-334. [ Ref ]

14. Nasir D, Gasanova I, Drummond S, Alexander J, Howard J, et al. (2017) Clonidine, but not Dexamethasone, Prolongs Ropivacaine- Induced Supraclavicular Brachial Plexus Nerve Block Duration. CurrClinPharmacol 12: 92-98. [ Ref ]

15. Droog W, Lin DY, Huisman JS, Franssen FA, van Aggelen GP, et al. (2017) Individual duration of axillary brachial plexus block is unpredictable: a prospective double centered observational study. Minerva Anestesiol 83: 1146-1151. [ Ref ]

16. Watanabe K, Tokumine J, Lefor AK, Moriyama K, Sakamoto H, et al. (2017) Postoperative analgesia comparing levobupivacaine and ropivacaine for brachial plexus block: A randomized prospective trial. Medicine (Baltimore) 96: e6457. [ Ref ]

17. Venkatesh RR, Kumar P, Trissur RR, George SK (2016) A Randomized Controlled Study of 0.5% Bupivacaine, 0.5% Ropivacaine and 0.75% Ropivacainefor Supraclavicular Brachial Plexus Block. J Clin Diagn Res 10: UC09-UC12.  [ Ref ]

18. Heinonen JA, Schramko AA, Skrifvars MB, Litonius E, Backman JT, et al. (2017) The effects of intravenous lipid emulsion on hemodynamic recovery and myocardial cell mitochondrial function after bupivacaine toxicity in anesthetized pigs. Hum ExpToxicol36:365-375. [ Ref ]

19. Park J, Kim YA, Han JY, Jin S, Ok SH, et al. (2016) Lipofundin® MCT/ LCT 20% increase left ventricular systolic pressure in an ex vivo rat heart model via increase of intracellular calcium level. Korean J Anesthesiol69:57-62.  [ Ref ]

20. Mamou Z, Descotes J, Chevalier P, Bui-Xuan B, Romestaing C, et al. (2015) Electrophysiological, haemodynamic, and mitochondrial alterations induced by levobupivacaine during myocardial ischemia in a pig model: protection by lipid emulsions? FundamClinPharmacol29:439-49. [ Ref ]

21. Fettiplace MR, Pichurko A, Ripper R, Lin B, Kowal K, et al. (2015) Cardiac depression induced by cocaine or cocaethylene is alleviated by lipid emulsion more effectively than by sulfobutylether-β-cyclodextrin. AcadEmerg Med22:508-517.  [ Ref ]

22. Dubé JJ, Coen PM, DiStefano G, Chacon AC, Helbling NL, et al. (2014) Effects of acute lipid overload on skeletal muscle insulin resistance, metabolic flexibility, and mitochondrial performance. Am J Physiol Endocrinol Metab15: 307. [ Ref ]

Lipid Emulsion for Local Anesthesia Reversal (LAR) after Prolonged Spinal/Epidural Anesthesia

List of Author(s): Joseph Eldor, Nguyen TA.

Abstract

A 71-year-old woman was scheduled for total knee replacement on left side. Combined Spinal Epidural Anesthesia (CSEA) was performed at L3-4 and L2-3 separately and was technically uneventful. Epidural Anesthesia (EA) with levobupivacaine 0.1%+fentanyl (2mcg/ml) was effective at 5 ml/h for postoperative analgesia. Eight hours post-op, she complained of having lost all feeling on the non-operative leg. On examination, she had diminished both touch sensory and motor power on the non-operative leg, but intact on the operative side with VAS at 2/10. Epidural catheter was receded 2 cm and the dose was lowered and paused. Despite of these adjustments after 4 hours, her experience was not improved. It was decided to use lipid emulsion as a challenging therapy. After completion of the lipid therapy, the sensory and movement of the non-operative leg regained normal after 60 min. The severe pain recurred which needed IV morphine titration. The EA of 2-5ml/h was recontinued and effective for pain control for 3 days without no incident.

It is the first time in the medical literature that Lipid Emulsion is used for the purpose of LAR (Local Anesthesia Reversal) not connected to LAST (Local Anesthetic Systemic Toxicity).

Keywords

Intralipid; Lipid emulsion; Fat emulsion; Local anesthesia reversal; Spinal anesthesia; Epidural anesthesia

Case Report

A 71-year-old woman was scheduled for total knee replacement on left side. Past medical history was hypertension, type 2 diabetes, bilateral degenerative knee pain. Combined Spinal Epidural Anesthesia (CSEA) was performed at L3-4 and L2-3 separately and was technically uneventful. Spinal Anesthesia (SA) with 10 mg bupivacaine 0.5% heavy+20mcg fentanyl was effective for surgery. Epidural Anesthesia (EA) with levobupivacaine 0.1%+fentanyl (2mcg/ml) was effective at 5ml/h for postoperative analgesia. She was sent back to ward after free movement of both knees. Eight hours post-op, she complained of having lost all feeling on the non-operative leg. On examination, she had diminished both touch sensory and motor power on the non-operative leg, but intact on the operative side with VAS at 2/10. After Local Anesthetic Systemic Toxicity (LAST) was ruled out, epidural catheter was receded 2cm and the dose was lowered and paused. Despite of these adjustments after 4 hours, her experience was not improved.

It was decided to use lipid emulsion as a challenging therapy. A vial of 250ml of Lipidem 20% (B. Braun) was infused over 30 min as regimen in ASRA's checklist for treatment of LAST. After completion of the lipid therapy, the sensory and movement of the non-operative leg regained normal after 60min. The severe pain recurred which needed IV morphine titration. The EA of 2-5ml/h was recontinued and effective for pain control for 3 days without no incident.

Discussion

LAST

On April 1998 Weinberg GL et al. published in Anesthesiology journal the following article: Pretreatment or resuscitation with a lipid infusion shifts the dose-response to bupivacaine-induced asystole in rats [1]. This article started the Intralipid (lipid infusion) LAST (Local Anesthetic Systemic Toxicity) treatment by Intralipid.

The article conclusion was that "Lipid infusion shifts the dose-response to bupivacaine-induced asystole in rats. Partitioning of bupivacaine into the newly created lipid phase may partially explain this effect. These results suggest a potential application for lipid infusion in treating cardiotoxicity resulting from bupivacaine".

On February 2018 Neal JM et al. published in Regional Anesthesia Pain Medicine journal the following article: The Third American Society of Regional Anesthesia and Pain Medicine Practice Advisory on Local Anesthetic Systemic Toxicity: Executive Summary 2017 [2].

The article conclusion was: "This interim update summarizes recent scientific findings that have enhanced our understanding of the mechanisms that lead to lipid emulsion reversal of LAST, including rapid partitioning, direct inotropy, and post-conditioning. Since the previous practice advisory, epidemiological data have emerged that suggest a lower frequency of LAST as reported by single institutions and some registries, nevertheless a considerable number of events still occur within the general community. Contemporary case reports suggest a trend toward delayed presentation, which may mirror the increased use of ultrasound guidance (fewer intravascular injections), local infiltration techniques (slower systemic uptake), and continuous local anesthetic infusions. Small patient size and sarcopenia are additional factors that increase potential risk for LAST. An increasing number of reported events occur outside of the traditional hospital setting and involve nonanesthesiologists".

The LAST was the subject regarding Intralipid and nothing else in all these 20 years of research. Eldor defined this Intralipid (fat emulsion containing soybean oil and egg yolk) as a "Magic Bullet" [3].

The case report mentioned in this article is a kind of a Local Anesthesia Reversal (LAR) by Intralipid. It is the first article mentioning this Intralipid – LAR treatment in the medical literature.

AFE

There are other theoretical options for use of intralipid. For example:

Lipid emulsion rescue of amniotic fluid embolism induced cardiac arrest: "As a last resort, IV lipid 20% emulsion (1.5mL/kg) was administered as a bolus [4]. Within 30 to 90 seconds, the patient had return of spontaneous circulation, normal sinus rhythm, and dramatic improvement in left and right ventricular function, shown clearly by TEE. After several minutes, the patient's condition slowly deteriorated once again to asystole, at which time CPR was once again started and a second lipid emulsion bolus (1.5mL/kg) was administered and followed with an infusion at 0.25mL/kg/min. Within 30 to 60 seconds, the patient again had a return of spontaneous circulation with normal sinus rhythm. In addition, she also exhibited spontaneous movements of her extremities".

"Although Eldor et al. were the first to suggest a possible benefit of lipid emulsion therapy in the treatment of AFE, this is the first published instance in which a patient received intravenous lipid emulsion temporally related to the recovery from cardiovascular collapse associated with amniotic fluid embolism [3]. The main limitation is the fact that AFE is a diagnosis of exclusion; however, other differential diagnoses are less likely. There is TEE evidence that shows overall improvement of cardiac function temporally related to administration of lipid emulsion. The patient had return of spontaneous circulation occurring shortly after the administration of lipid emulsion on 2 different occasions after exhausting all other ACLS options, suggesting that lipid emulsion may have been responsible for the successful resuscitation. In addition, after the initial improvement, a relapse occurred, which was treated with a second bolus of lipid emulsion after which the same improvement in clinical and cardiac function occurred. Full neurologic recovery was noted after significantly prolonged cardiovascular collapse with chest compressions (40 min) and exhaustion of other standard ACLS medications. The excellent neurologic recovery emphasizes the importance of high quality and sustained CPR. Furthermore, a possible physiologic mechanism for the cardiopulmonary recovery is presented and is based on scientific models from previous research on the effects of lipid emulsion and its components. This report suggests a possible benefit of lipid emulsion therapy in the treatment of cardiovascular collapse caused by AFE, and further research will be required to elucidate the role of lipid emulsion therapy in the setting of AFE".

Spinal/Epidural Lavage

This study was designed to determine whether epidural motor blockade could be reversed by postoperative injections of crystalloid solutions via the epidural catheter [5]. Twenty-seven patients (ASA physical status I, nonlabouring) had epidural anesthesia with 0.75% bupivacaine for elective cesarean delivery. Postoperatively, patients were randomized to receive three 15mL injections (over 30 min) of crystalloid solutions (normal saline or Ringer's lactate) or no treatment (control) via the epidural catheter. Degree of motor and sensory blockade was evaluated with an investigator blinded to treatment group. Rate of resolution of sensory blockade was not different among groups. However, time for resolution of motor blockade was more than twice as long in the control group than in either treatment group (control=178 +/- 70 min vs Ringer's lactate=84 +/- 44 min, normal saline=70 +/- 38 min, P=0.001). The data suggest that unwanted motor blockade due to epidural anesthesia can be reversed by epidural injections of crystalloid solutions [5].

Prolonged motor and sensory block following epidural anesthesia can be associated with extended postoperative care unit stays and patient dissatisfaction. Previous studies have demonstrated a more rapid motor recovery following the administration of epidural crystalloids in patients who had received plain bupivacaine and lidocaine epidural anesthesia. However, epinephrine is commonly added to local anesthetics to improve the quality and prolong the duration of the epidural block. The objective of this study was to determine the relationship of 0.9% NaCl epidural catheter flush volume (i.e., washout) to the recovery of motor and sensory block in patients undergoing 2% lidocaine with epinephrine epidural anesthesia [6].

A prospective, randomized, double-blind study design was utilized. Thirty-three subjects scheduled for elective gynecologic or obstetrical surgical procedures underwent epidural anesthesia using 2% lidocaine with epinephrine (1:200,000). A T4 dermatome level of analgesia, determined by toothpick prick, was maintained intraoperatively. Following surgery, subjects were randomized to 1 of 3 treatment groups. Group 1 (control, n=11) received no epidural 0.9% NaCl (normal saline [NS]) postoperatively.

Group 2 (15 mL NSx1, n=10) received an epidural bolus of 15 mL NS. Group 3 (15 mL NSx2, n=12) received an epidural bolus of 15 mL NS postoperatively and a second 15 mL NS bolus 15 minutes later. Assessment of motor and sensory block was performed at 15-minute intervals until complete motor and sensory recovery.

Times to partial and full motor and sensory recovery were significantly faster in the epidural NS groups than in the control group. Full motor recovery was more rapid in subjects receiving two 15 mL NS epidural NS boluses (30 mL total) compared with those receiving a single 15-mL NS bolus (108 +/- 9 min vs 136 +/- 13 min) and significantly faster than control group subjects (153 +/- 14 min). Both NSx1 and NSx2 epidural bolus groups experienced significantly reduced times to complete sensory recovery when compared with the control group (NSx1=154 +/- 13 min, NSx2=153 +/- 9 min, control 195 +/- 14 min).

A more rapid recovery of motor and sensory block in patients undergoing 2% lidocaine with epinephrine epidural anesthesia can be achieved with the use of 30 mL NS epidural washout [6].

In this case report, we describe the use of cerebrospinal fluid lavage as a successful treatment of an inadvertent intrathecally placed epidural catheter in a 14-yr-old girl who underwent a combination of epidural anesthesia and general anesthesia for orthopedic surgery [7]. In this case, a large amount of local anesthetic was injected (the total possible intrathecal injection was 200 mg of lidocaine and 61 mg of bupivacaine), resulting in apnea and fixed dilated pupils in the patient at the end of surgery. Twenty milliliters of cerebrospinal fluid was replaced with 10 mL of normal saline and 10 mL of lactated Ringer's solution from the "epidural" catheter. Spontaneous respiration returned 5 min later, and the patient was tracheally extubated after 30 min. No signs of neurological deficit or post dural puncture headache were noted after surgery.

Cerebrospinal lavage may be a helpful adjunct to the conventional supportive management of patients in the event of an inadvertent total spinal [7].

Several investigators have described the phenomena of epidural saline washout using bolus injections. This study was designed to determine whether epidural block could be reversed more effectively by infusion of crystalloid solutions via the epidural catheter.

One hundred male patients scheduled for outpatient surgery were enrolled in this study. After 30 min of 2% prilocaine epidural anesthesia, patients were randomly assigned to receive 45 mL of study solution as follows: (1) normal saline bolus (group NSB); (2) Ringer's lactate bolus (group RLB); (3) normal saline infusion (group NSI); (4) Ringer's lactate infusion (group RLI). Patients in the control group received no washout fluid. Motor, sensory blockade and side effects were compared among 5 groups. Ambulation time is defined as the recovery time.

In the control group, ambulation time (139 +/- 15 min) was significantly longer than in the washout groups (NSB 90 +/- 10, RLB 88 +/- 10, NSI 85 +/- 8, RLI 91 +/- 6 minutes) (P<0.001). Two-segment sensory regression time in the control group (86 +/- 15 min) was significantly longer than in groups NSB, RLB, NSI and RLI (55 +/- 8, 51 +/- 4, 58 +/- 8, and 53 +/- 10 minutes, respectively) (P<0.001).

We concluded that a more rapid recovery of motor and sensory blockade in patients undergoing epidural anesthesia may be achieved by the use of an epidural washout with either bolus or infusion of 45 mL normal saline or Ringer's lactate [8].

High or total spinal anesthesia commonly results from accidental placement of an epidural catheter in the intrathecal space with subsequent injection of excessive volumes of local anesthetic. Cerebrospinal lavage has been shown to be effective at reversing the effects of high/total spinal anesthesia but is rarely considered in obstetric cases. Here, we describe the use of cerebrospinal lavage to prevent potential complications from high/total spinal anesthesia after unintentional placement of an intrathecal catheter in a labouring obstetric patient [9].

A 34-yr-old female presented to the labour and delivery unit in active labour. Epidural anesthesia was initiated, and after the first bolus dose, the patient experienced lower extremity motor block and shortness of breath. A high spinal was confirmed, and cerebrospinal lavage was performed. In total, 40 mL of cerebrospinal fluid (CSF) were exchanged for an equal volume of normal saline. The patient's breathing difficulties and motor block resolved quickly, and a new epidural catheter was placed after removal of the spinal catheter. Pain control was effective, and the patient delivered a healthy baby.

We show that exchange of CSF for normal saline can be used successfully to manage a high spinal in an obstetric patient [9]. Our results suggest that CSF lavage could potentially be an important and helpful adjunct to the conventional supportive management of obstetric patients in the event of inadvertent high or total spinal anesthesia [9].

Dental LAR

PM (OraVerse) enables the dentist or dental hygienist (where permitted) to significantly decrease the duration of residual STA in patients where such numbness may prove to be potentially injurious (children, geriatric, and special needs patients), or a negative influence on their quality of life (speaking, eating, negative body image). (Note: As of August 3, 2009, dental hygienists are permitted to administer PM in the following states: Alaska, Arkansas, Hawaii, Idaho, Iowa, Louisiana, Montana, Nevada, New York, North Dakota, Oklahoma, Rhode Island, Tennessee, Utah, and Wisconsin) [10].

This study sought to identify and quantify complications with local anesthetic administration and reversal on consecutive patients seen for comprehensive dental care in a school-based, portable dental clinic, and includes data on the patients seen by the participating portable dental providers. In 923 dental visits where local anesthetic was administered, a standardized form was used to gain further information and identify any complications; this was accompanied by a questionnaire for the student's teacher, in order to quantify the student's distraction and disruption ratings following the dental visit. After statistical analysis of the 923 consecutive cases, the overall complication rate was 5.3%. All of the complications were considered to be mild or moderate, and there were no severe event reports. The complications encountered most frequently (n=49) were associated with self-inflicted soft tissue injury. The results of this study indicate that comprehensive care with local anesthesia delivered by a school-based portable dental clinic has a low risk of complications. Whereas safe administration of dental care is achievable with or without phentolamine mesylate as a local anesthetic reversal agent, its use was determined to improve safety outcomes. Three factors appeared to directly increase the incidence of complications: the administration of an inferior alveolar nerve block, attention deficit disorder, and obesity. Teacher evaluations demonstrated that children receiving care by a portable dental team were able to reorient back to class work and were not disruptive to classmates [11].

Administration of local anesthesia is an integral procedure prior to dental treatments to minimize the associated pain. It is learned that its effect stays more than the time required for the dental procedure to be completed. This prolonged soft tissue anesthesia (STA) can be detrimental, inconvenient, and unnecessary.

Phentolamine mesylate, a Food and Drug Administrationapproved drug essentially serves the purpose of faster recovery from numbness at the site of local anesthesia. This article reviews the development of the drug phentolamine mesylate and its indication as a local anesthetic reversal agent [12]. A literature search for phentolamine mesylate as a STA reversal agent was conducted in PubMed using the terms "dental local anesthesia reversal, phentolamine mesylate" up to March 2014. The search was limited to articles published in English. The search revealed 13 PubMed indexed articles stating the development and application of phentolamine mesylate. Phentolamine mesylate is an important step in the progress of developing patient care as well as an aid to the dental clinician [12].

Lipid emulsion for non-local anesthetics toxicity

The use of intravenous lipid emulsion (ILE) therapy for the treatment of lipophilic drug toxicity is increasing. Despite this, the evidence for its effect in non-local anesthetic toxicity remains sparse. Furthermore, many case reports describe ILE use for substances in which no clear efficacy data exists. The American Academy of Clinical Toxicology established a lipid emulsion workgroup. The aim of this group is to review the available evidence regarding the effect of ILE in non-LA drug poisoning and develop consensus-based recommendations on the use of this therapy.

A systematic review of the literature was performed to capture articles through 15 December 2014. Relevant articles were determined based upon a predefined methodology. Articles involving pre-treatment experiments, pharmacokinetic studies not involving toxicity, and studies not addressing antidotal use of ILE met pre-defined exclusion criteria. Agreement of at least two members of the subgroup was required before an article could be excluded.

The final analysis included 203 articles: 141 for humans and 62 for animals. These include 40 animal experiments and 22 case reports involving animal toxicity. There were three human randomized control trials (RCT): one RCT examined ILE in TCA overdose, one RCT examined ILE in various overdoses, and one study examined ILE in reversal of sedation after therapeutic administration of inhaled anesthesia. One observational study examined ILE in glyphosate overdose. In addition, 137 human case reports or case series were identified. Intravenous lipid emulsion therapy was used in the management of overdose with 65 unique substances.

Despite the use of ILE for multiple substances in the treatment of patients with poisoning and overdose, the effect of ILE in various non-local anesthetic poisonings is heterogenous, and the quality of evidence remains low to very low [13].

IRE (Intralipid Rescue Evidence)

The quality of "evidence" related to case reports cannot be "low to very low" unless there is "evidence" that the authors fabricated the facts of the case.

We do not think that anyone in any Practice Advisory in any Executive Summary has any proof to delete any evidence from any case report.

This is what makes Intralipid (or any other fat emulsion with soybean oil and egg yolk) a "magic bullet": "Intravenous lipid emulsion therapy was used in the management of overdose with 65 unique substances".

Does anyone know of another substance that can reverse the toxicity of 65 unique substances? and this is only the beginning.

Conclusion

It is the first time in the medical literature that Lipid emulsion is used for the purpose of LAR (Local Anesthesia Reversal) not connected to LAST (Local Anesthetic Systemic Toxicity).

### References

1.  Weinberg GL, VadeBoncouer T, Ramaraju GA, Garcia-Amaro MF, Cwik MJ (1998) Pretreatment or resuscitation with a lipid infusion shifts the dose-response to bupivacaine-induced asystole in rats. Anesthesiology 88: 1071-1075.

2.  Neal JM, Barrington MJ, Fettiplace MR, Gitman M, Memtsoudis SG, et al. (2018) The third american society of regional anesthesia and pain medicine practice advisory on local anesthetic systemic toxicity: executive summary 2017. Reg Anesth Pain Med 43: 113-123.

3. Joseph Eldor (2017) Intalipid–A Magic Bullet?

4.  Windrik Lynch MD, Russell K, Jack F, William C, Culp Jr (2017) Lipid Emulsion Rescue of Amniotic Fluid Embolism Induced Cardiac Arrest: A Case Report. A&A Case Reports 8: 64-66.

5. Johnson MD, Burger GA, Mushlin PS, Arthur GR, Data S (1990) Reversal of bupivacaine epidural anesthesia by intermittent epidural injections of crystalloid solutions. Anesth Analg 70: 395-399.

6.  Sitzman BT, DiFazio CA, Playfair PA, Stevens RA, Hanes CF, et al. (2001) Reversal of lidocaine with epinephrine epidural anesthesia using epidural saline washout. Reg Anesth Pain Med 26: 246-251.

7.  Tsui BC, Malherbe S, Koller J, Aronyk K (2004) Reversal of an unintentional spinal anesthetic by cerebrospinal lavage. Anesth Analg 98: 434-436.

8.  Katircioglu K, Ozkalkanli MY, Kalfaoglu H, Sannav S, Ozgurbuz U, et al. (2007) Reversal of prilocaine epidural anesthesia using epidural saline or ringer's lactate washout. Reg Anesth Pain Med 32: 389-392.

9. Ting HY, Tsui BC (2014) Reversal of high spinal anesthesia with cerebrospinal lavage after inadvertent intrathecal injection of local anesthetic in an obstetric patient. Can J Anaesth 61: 1004-1007.

10. Malamed SF (2010) Local anesthesia reversal. Dent Today 29: 65-66.

11. Boynes SG, Riley AE, Milbee S, Bastin MR, Price ME, et al. (2013) Evaluating complications of local anesthesia administration and reversal with phentolamine mesylate in a portable pediatric dental clinic. Gen Dent 61: 70-76.

12.  Grover HS, Gupta A, Saksena N1, Saini N (2015) Phentolamine mesylate: It's role as a reversal agent for unwarranted prolonged local analgesia. J Indian Soc Pedod Prev Dent 33: 265-268.

13.  Levine M, Hoffman RS, Lavergne V, Stork CM, Graudins A, et al. (2016) Lipid Emulsion Workgroup. Systematic review of the effect of intravenous lipid emulsion therapy for non-local anesthetics toxicity. Clin Toxicol (Phila) 54: 194-221.

Lipid Emulsion Treatment for Post Spinal Anesthesia Myoclonus

List of Author(s): Nguyen TA, Phan DV, Dang TT, Joseph Eldor.

Abstract

Two case reports of myoclonus of legs post spinal anesthesia treated successfully by IV lipid emulsion are first described in the medical literature.

A review of cases of myoclonus post regional anesthesia (spinal or epidural) are discussed with the hypothesis that the Lipid Emulsion effects are on the mitochondria and the intracellular calcium.

Keywords

Myoclonus; Post spinal anesthesia myoclonus; Post epidural anesthesia myoclonus; Intralipid; Lipidem; Fat emulsion; Mitochondria; Intracellular calcium

Case Report No 1

43-years-old, healthy female patient was scheduled for drainage of an abcess on the right buttock. In the past she had given 2 Spinal Anesthesia for Cesarian sections uneventfully. For surgery this time, Spinal Anesthesia performed at L3-4 with 6 mg bupivacaine 0.5% heavy and 20 mcg fentanyl uneventfully. Time of surgery was 30 min. Myoclonic movement of both legs occurred 60 min post-op. She remained fully conscious and had no other local neurological symptoms. Vital signs were stable. LAST was ruled out. She was under close monitoring, but myoclonus was not diminished in 2 hours. Lipid challenging therapy was considered. After an infusion of 250 ml Lipidem 20% over 30 min abnormal movement diminished gradually and disappeared in 60 min. No recurrent of myoclonus episode was noted thereafter.

The patient's myoclonus can be seen in the following video [23]:

Case Report No 2

A female 34 years-old, 39 weeks of pregnancy. Her precedent had two vaginal delivery (the second time with the assistance of Forceps). She was healthy and had expected a normal delivery but failed. The Cesarian section was performed under Spinal Anesthesia. The 27 Quincke Needle was introduced at L3-4 uneventfully. Dose of SA was 7.5 mg Bupivacaine heavy 0.5% (Aguettant)+25 mcg Fentanyl. The operation lasted 45 min without any medication added. Approximately 100 min postop, patient had myoclonus on the left leg as in the following Video [24].

The movement of the right leg was normal. The sensory feeling of both legs returned nearly normal. Other systems were with no particular problems. No LAST, hemodynamic was stable, she was totally conscious, no shivering, no other neurological signs.

Since the anesthesiologist (TTD) learned from anesthesiologist (TAN) his case through discussions in the group on Facebook, he used LIPIDEM 20% (B. Braun) right away, not wasted time as in anesthesiologist (TAN) case (case no.1). After 5 min of IV Lipid emulsion infusion the myoclonus decreased significantly (see the video after Lipidem infusion) [25]. and gone away in 30 min of the IV lipid emulsion infusion.

Discussion

Lipidem

Lipidem is an intralipid like lipid emulsion (using Soybean oil and Egg yolk) with the following composition

Lipoplus®/ Lipidem® Composition 1000 ml of emulsion contains: Medium-chain triglycerides: 100.0 g Soybean oil, refined: 80.0 g Omega-3-acid triglycerides: 20.0 g Essential fatty acid content per liter: Linoleic acid (omega-6): 48.0-58.0 g Alpha-linolenic acid (omega-3): 5.0-11.0 g Eicosa-pentaenoic acid and docosahexaenoic acid: 8.6-17.2 g Caloric content per liter: 7,900 kJ ≈ 1,910 kcal. Osmolality: approx. 410 mOsm/kg. Titration acidity or alkalinity (to pH 7.4): less than 0.5 mmol/l NaOH or HCl pH: 6.5-8.5. The other ingredients are glycerol, egg lecithin, allrac- α-Tocopherol, ascorbyl palmitate, sodium oleate, sodium hydroxide (for pH adjustment) and water for injections. B. Braun Melsungen AG Carl-Braun-Straße 134212 Melsungen, Germany.

Myoclonus

Myoclonus creates significant disability for patients. This symptom or sign can have many different etiologies, presentations, and pathophysiological mechanisms. A thorough evaluation for the myoclonus etiology is critical for developing a treatment strategy. The best etiological classification scheme is a modified version from that proposed by Marsden et al. in 1982. Clinical neurophysiology, as assessed by electromyography and electroencephalography, can be used to classify the pathophysiology of the myoclonus using a neurophysiology classification scheme. If the etiology of the myoclonus cannot be reversed or treated, then symptomatic treatment of the myoclonus itself may be warranted. Unfortunately, there are few controlled studies for myoclonus treatments.

The treatment strategy for the myoclonus is best derived from the neurophysiology classification scheme categories:

1. cortical,

2. cortical-subcortical,

3. subcortical-nonsegmental,

4. peripheral.

A cortical physiology classification is most common. Levetiracetam is suggested as first-line treatment for cortical myoclonus, but valproic acid and clonazepam are commonly used. Cortical-subcortical myoclonus is the physiology demonstrated by myoclonic seizures, such as in primary epileptic myoclonus (e.g., juvenile myoclonic epilepsy). Valproic acid has demonstrated efficacy in such epileptic syndromes with other medications providing an adjunctive role. Clonazepam is used for subcorticalnonsegmental myoclonus, but other treatments, depending on the syndrome, have been used for this physiological type of myoclonus. Segmental myoclonus is difficult to treat, but clonazepam and botulinum toxin are used. Botulinum toxin is used for focal examples of peripheral myoclonus. Myoclonus treatment is commonly not effective and/or limited by side effects [1].

Myoclonus remains a challenging movement phenotype to characterize, evaluate, and treat. A systematic assessment of the temporal sequence, phenomenology, and distribution of movements can assist in the rational approach to diagnosis and management.

Cortical forms of myoclonus are increasingly recognized as primarily cerebellar disorders. A syndrome of orthostatic myoclonus has been recognized by electrophysiology in patients with neurodegenerative disorders, mainly in Alzheimer disease, accounting for impairments in gait and balance previously mischaracterized as normal pressure hydrocephalus or orthostatic tremor. Tyrosine hydroxylase deficiency and Silver-Russell syndrome (uniparental disomy of chromosome 6) have been established as two novel causes of the myoclonus-dystonia syndrome. Mutations in the glycine receptor (GlyR) α1-subunit gene (GLRA1) explain the major expression of hyper ekplexia, an inherited excessive startle disorder, but newly identified mutations in GlyR β-subunit (GLRB) and glycine transporter 2 (GlyT2) genes (SLC6A5) account for "minor" forms of this disorder manifested as excessive startle and hypnic jerks. The entity previously known as palatal myoclonus has been reclassified as palatal tremor in recognition of its clinical and electromyographic features and no longer enters the differential diagnosis of myoclonic disorders. Increasing documentation of psychogenic features in patients previously characterized as having propriospinal myoclonus has cast doubts on the existence of this distinctive disorder.

Myoclonus can be a prominent manifestation of a wide range of disorders. Electrophysiologic testing aids in distinguishing myoclonus from other mimics and classifying them according to cortical, subcortical, or spinal origin, which assists the choice of treatment. Despite the lack of randomized clinical trials, levetiracetam appears most effective in patients with cortical myoclonus, whereas clonazepam remains the only first-line therapeutic option in subcortical and spinal myoclonus [2].

Post spinal/epidural anesthesia myoclonus

Perioperative spinal myoclonus is extremely rare. Many anaesthetists and perioperative practitioners may not diagnose or manage this complication appropriately when it occurs. This case report of unusual acute spinal myoclonus following regional anaesthesia highlights certain aspects of this rare complication that have not previously been published [3].

A series of four consecutive patients who developed acute lower-limb myoclonus following spinal or epidural anaesthesia are described. The case series occurred at three different hospitals and involved four anaesthetists over a 3-year period. Two Caucasian men, aged 90-years-old and 67-years-old, manifested unilateral myoclonus. Two Caucasian women, aged 64-years-old and 53-years-old, developed bilateral myoclonus. Myoclonus was self-limiting in one patient, treated with further regional anaesthesia in one patient and treated with intravenous midazolam in two patients. The overall outcome was good in all patients, with no recurrence or sequelae in any of the patients.

This case series emphasizes that spinal myoclonus following regional anaesthesia is rare, has diverse pathophysiology and can have diverse presentations. The treatment of perioperative spinal myoclonus should be directed at the aetiology. Anaesthetists and perioperative practitioners who are unfamiliar with this rare complication should be reassured that it may be treated successfully with midazolam [3].

We report a case of spinal myoclonus induced by the tip of an intrathecal catheter in a 35-year-old patient with severe, adult-onset, generalized dystonia of unknown cause, treated for 2 years using intrathecal baclofen [3]. One month after a falling episode, the patient developed focal myoclonus of the right proximal leg whenever she stood up from a seated position. The electrophysiologic recordings were compatible with spinal segmental myoclonus, originating at a focus corresponding to the L2-S2 segments. At this site, the tip of the intrathecal catheter was demonstrated by myelography to be in close proximity to the nerve roots and conus medullaris. The myoclonus resolved promptly once the catheter tip was withdrawn. This report represents an unusual complication of intrathecal catheter systems that, if recognized, can lead to prompt therapeutic intervention [4].

A nulliparous woman presented with pre-eclampsia at 39 weeks' gestation. A combined spinal-epidural anaesthesia was employed for Caesarean section, but the spinal component produced no discernible block, so the epidural was topped up with 20 ml ropivacaine 0.75% without problem and surgery was uneventful. A week after delivery she developed twitching of her legs and opisthotonus, that was initially thought to be eclampsia but was subsequently diagnosed as spinal myoclonus. She was treated with oral carbamazepine and diazepam, with improvement over the next 4 days, and discharged home a week later taking oral carbidopa and levodopa. Her symptoms resolved completely 6 months after the initial event [5].

We report a patient who developed paraplegia following percutaneous nephrolithotresis of the left kidney under epidural anaesthesia [6]. The cause of the paraplegia was unknown, but occlusion of the anterior spinal artery or central arteries and arachnoiditis, possibly due to the epidural anaesthesia, may have taken part in the onset and progression of the paralysis. The patient had spinal myoclonus corresponding to the spinal levels where myelomalacia was found by magnetic resonance (MR) imaging [6]. Spinal myoclonus following neuraxial anesthesia is rare. This report describes a case of myoclonus-like involuntary movement that occurred during the recovery from epidural anesthesia for a cesarean delivery. The patient's symptom improved with the administration of benzodiazepine, and the patient recovered with no neurological sequelae. In conclusion, epidural anesthesia can cause spinal myoclonus, which can be treated with a benzodiazepine [7].

Involuntary movement during and after neuraxial anesthesia, such as spinal and epidural anesthesia, is rarely observed. In this report, we describe a case of myoclonus-like involuntary movement of the upper extremities in a patient undergoing a planned repeat cesarean section under spinal anesthesia with bupivacaine that completely subsided after administration of 2 mg of midazolam [8]. The myoclonus-like movement did not recur or cause any apparent neurological side effects [8].

It is presented in this case report a very rare complication after spinal anesthesia to provide subsidies to the management and therapeutic conduct [9]. This is a 63-year old African-Brazilian patient, ASA I, scheduled for transurethral resection of the prostate (TURP). He underwent subarachnoid anesthesia with bupivacaine (15 mg) without adrenaline. Intercurrences were not observed during puncture, and the patient was positioned for surgery. Soon after positioning the patient, he complained of severe pain in the perineum region followed by involuntary tonicclonic movements of the lower limbs. The patient was treated with a benzodiazepine to control the myoclonus without response. This episode was followed by significant agitation and the patient was intubated. He was maintained in controlled ventilation and transferred to the Intensive Care Unit. Despite all biochemical and imaging tests performed, an apparent cause was not detected. The medication was not changed and the same batch of anesthetic had been used in other patients that same day without intercurrences.

After ruling out all possible causes, the diagnosis of spinal myoclonus after spinal anesthesia with bupivacaine was made by exclusion [9]. Spinal myoclonus is an unusual, self-limiting, adverse event that may occur during spinal anesthesia. The exact cause and underlying biochemical mechanism of spinal myoclonus remain unclear. A few cases of spinal myoclonus have been reported after administration of intrathecal bupivacaine. We report a case in which spinal myoclonus recurred after two episodes of spinal anesthesia with bupivacaine at a 1-year interval in a 35-year-old woman [10]. The myoclonus was acute and transient. The patient recovered completely, with no neurologic sequelae [10].

We report a case of spinal myoclonus following cesarean section [11]. The patient was a 34-year-old woman without history of neurologic disorders. In the operating room, after placement of an epidural catheter at T12-L1, bupivacaine 2.4 ml was administered intrathecally via a 25 G needle at L2-3. Epidural administration of ropivacaine (0.13%, 4 ml x hr(-1)) was started 72 min after spinal anesthesia. The intraand postoperative courses were otherwise uneventful. The patient complained of involuntary jerky movements of her lower legs 195 min after the start of the spinal anesthesia. The sensory level was T12 and she could move her legs on command but could not stop her involuntary movements. The myoclonic movements ceased 150 min later without medication and did not reappear, despite restarting the epidural anesthesia with ropivacaine [11].

Propriospinal myoclonus is a rare disorder characterized by sudden, shock-like, involuntary jerks that arise from the axial muscles and spread both rostrally and caudally to other myotomes through slow polysynaptic pathways. It can be idiopathic or secondary to intrinsic and extrinsic spinal cord lesions; additionally, it can develop as an adverse effect to the administration of several drugs, including neuraxial local anesthetics. This article describes a case of transient propriospinal myoclonus in a 77-year-old woman undergoing surgery for hip replacement who received 12 mg of 0.5% normobaric bupivacaine administered by a 25-G spinal needle [12]. On postoperative day 1, the patient presented with spinal myoclonus, defined by clinical and electrophysiologic studies. Valproate and clonazepam controlled the symptoms, and on day 4 the myoclonus completely disappeared. Few cases of myoclonus induced by intrathecal bupivacaine administration have been reported in the literature, but systematic reviews written to clarify the global incidence and the physiopathology of this complication are still lacking [12].

Focal myoclonus of peripheral origin, i.e., peripheral myoclonus (PM), is a rare disorder. Although PM always accompanies a lesion in the peripheral nerve, supplying the affected muscles, its mechanism remains unclear. Here we present a patient with focal myoclonus of the thigh muscles following a traumatic lesion in the femoral nerve [13]. Lumbar spinal anesthesia, as well as local anesthetic block of the femoral nerve, completely abolished the patient's myoclonus temporarily. This movement was remarkably diminished after a surgical exploration of the wound with the removal of fibrous tissue beneath the scar and liberation of the femoral nerve. This case suggests the contribution of a spinal relay mechanism in the development of PM, in addition to the contribution of a nerve lesion [13].

We report a patient who developed a rare neurological complication of spinal myoclonus possibly caused by an epidural catheter [14]. A 24-yr-old female received laparoscopy and intrauterine curettage under general combined with epidural anesthesia. Spinal myoclonus started about 4 hours after the last epidural drug injection and disappeared 2 hours following removal of the epidural catheter. The patient was discharged without any untoward neurological sequelae [14].

We herein report a case of spinal myoclonus following the administration of epidural anesthesia [15]. A 25-year-old woman underwent lumbar epidural anesthesia because of lumbago and cramps in her left lower limb. She immediately felt a lancinating pain in her left limb during anesthesia at the level of L 4/5 and soon developed myoclonus in her left thigh. The neurological examination revealed rhythmic myoclonus in the left quadriceps and adductor thigh muscles. The myoclonus disappeared after performing a blockade of the left L4 spinal root by using 1.5 ml of 1% lidocaine. An injury to the left L4 nerve root during the epidural anesthesia possibly caused an abnormal transmission of the impulses or ectopic hyperexcitability in the nerve root, which might lead to the disturbance of the spinal inhibitory interneurons and hyperexcitability of the anterior horn cells causing myoclonus. Since she did not demonstrate any muscular weakness, nor sensory loss during the lidocaine block, the 1% lidocaine appeared to block the sympathetic nerves or to suppress the ectopic hyperexcitability. The sympathetic nerves may be involved in the development of her spinal myoclonus [15].

The use of intrathecal diamorphine via an implanted portal system is described for pain control in a patient suffering from vertebral metastatic disease. The complication of myoclonic spasms affecting the lower half of the body occurred after 14 days, when increasing the bolus dose to 40 mg. The spasms lasted for 3 hr and then gradually subsided. Diamorphine was subsequently restarted at a lower dose of 15 mg twice daily. On increasing the dose to 20 mg diamorphine 10 days later, severe distressing myoclonic spasms recurred 20 min post injection. Myoclonus could only be controlled by instituting a local anesthetic intrathecal block. The patient was finally managed with 20 mg diamorphine per day by intrathecal infusion, and the pain was reasonably well controlled for the following 10 weeks without any recurrence of myoclonic spasms [16].

We report a case of periodic leg movements (PLM) observed in an 86-year-old man during either midthoracic epidural anesthesia or spinal anesthesia [17]. The PLM observed were stereotyped (extension of the big toe in combination with partial flexion of the ankle, knee, and hip lasting 3-5s) and repetitive (inter event intervals between jerks were 20-40s) for about 120 and 30 min respectively. The patient was awake but unaware of the PLM unless reminded. The present case was quite similar to sleep-related (noctural) myoclonus (SRM) in every respect except for its occurrence during wakefulness. SRM is more prevalent in the elderly population but its mechanism remains to be elucidated. Previously, we had reported a case of PLM observed in an elderly man with SRM [18]. In our two cases, PLM were seen only while the local anesthetic was acting on the spinal cord; therefore, these anesthesia-related PLM (ARPLM) may suggest that the spinal cord is involved. In particular, we consider that physiological changes seen commonly during non-rapid-eye-movement sleep and a certain phase of anesthesia, such as suppression of the descending inhibitory pathway, and pyramidal tract dysfunction are relevant to ARPLM. In addition, the concomitant alteration of the blood flow in the leg and changes due to aging of the spinal cord may also be involved [17].

Lipid emulsion effects on mitochondria and intracellular calcium

Local anesthetic toxicity is thought to be mediated partly by inhibition of cardiac mitochondrial function. Intravenous (i.v.) lipid emulsion may overcome this energy depletion, but doses larger than currently recommended may be needed for rescue effect. In this randomized study with anesthetized pigs, we compared the effect of a large dose, 4 mL/kg, of i.v. 20% Intralipid® (n=7) with Ringer's acetate (n=6) on cardiovascular recovery after a cardiotoxic dose of bupivacaine [18]. We also examined mitochondrial respiratory function in myocardial cell homogenates analyzed promptly after needle biopsies from the animals. Bupivacaine plasma concentrations were quantified from plasma samples. Arterial blood pressure recovered faster, and systemic vascular resistance rose more rapidly after Intralipid than Ringer's acetate administration (p<0.0001), but Intralipid did not increase cardiac index or left ventricular ejection fraction. The lipid-based mitochondrial respiration was stimulated by approximately 30% after Intralipid (p<0.05) but unaffected by Ringer's acetate. The mean (standard deviation) area under the concentrationtime curve (AUC) of total bupivacaine was greater after Intralipid (105.2(13.6) mg·min/L) than after Ringer's acetate (88.1(7.1) mg·min/L) (p=0.019). After Intralipid, the AUC of the lipid-un-entrapped bupivacaine portion (97.0(14.5) mg·min/L) was 8% lower than that of total bupivacaine (p<0.0001). To conclude, 4 mL/kg of Intralipid expedited cardiovascular recovery from bupivacaine cardiotoxicity mainly by increasing systemic vascular resistance. The increased myocardial mitochondrial respiration and bupivacaine entrapment after Intralipid did not improve cardiac function [18].

Lipid emulsions have been used to treat various drug toxicities and for total parenteral nutrition therapy. Their usefulness has also been confirmed in patients with local anesthetic-induced cardiac toxicity. The purpose of this study was to measure the hemodynamic and composition effects of lipid emulsions and to elucidate the mechanism associated with changes in intracellular calcium levels in myocardiocytes.

We measured hemodynamic effects using a digital analysis system after Intralipid® and Lipofundin® MCT/ LCT were infused into hearts hanging in a Langendorff perfusion system [19,20]. We measured the effects of the lipid emulsions on intracellular calcium levels in H9c2 cells by confocal microscopy.

Infusion of Lipofundin® MCT/LCT 20% (1 ml/kg) resulted in a significant increase in left ventricular systolic pressure compared to that after infusing modified Krebs- Henseleit solution (1 ml/kg) (P=0.003, 95% confidence interval [CI], 2.4-12.5). Lipofundin® MCT/LCT 20% had a more positive inotropic effect than that of Intralipid® 20% (P=0.009, 95% CI, 1.4-11.6). Both lipid emulsion treatments increased intracellular calcium levels. Lipofundin® MCT/ LCT (0.01%) increased intracellular calcium level more than that of 0.01% Intralipid® (P<0.05, 95% CI, 0.0-1.9).

These two lipid emulsions had different inotropic effects depending on their triglyceride component. The inotropic effect of lipid emulsions could be related with intracellular calcium level [19].

Accidental intravascular or high-dose injection of local anesthetics (LA) can result in serious, potentially lifethreatening complications. Indeed, adequate supportive measures and the administration of lipid emulsions are required in such complications.

The study's objectives were threefold:

(i) evaluate the myocardial toxicity of levobupivacaine when administered intravenously; (ii) investigate levobupivacaine toxicity on cardiomyocytes mitochondrial functions and cellular structure; (iii) assess the protective effects of a lipid emulsion in the presence or absence of myocardial ischemia. Domestic pigs randomized into two groups of 24 animals each, with either preserved coronary circulation or experimental myocardial ischemia. Six animals from each group received either: (i) single IV injection of saline, (ii) lipid emulsion (Intralipid (®)), (iii) levobupivacaine, (iv) combination levobupivacaine-Intralipid (®).

Serially measured endpoints included: heart rate, duration of the monophasic action potentials (dMAP), mean arterial pressure, and peak of the time derivative of left ventricular pressure (LV dP/dtmax). In addition, the following cardiomyocytes mitochondrial functions were measured: reactive oxygen species (ROS) production, oxidative phosphorylation, and calcium retention capacity (CRC) as well as the consequences of ROS production on lipids, proteins, and DNA. IV injection of levobupivacaine induced sinus bradycardia and reduced dMAP and LV dP/ dtmax. At the mitochondrial level, oxygen consumption and CRC were decreased. In contrast, ROS production was increased leading to enhanced lipid peroxidation and structural alterations of proteins and DNA. Myocardial ischemia was associated with global worsening of all changes. Intralipid (®) quickly improved haemodynamics. However, beneficial effects of Intralipid (®) were less clear after myocardial ischemia [20].

Cocaine intoxication leads to over 500,000 emergency department visits annually in the United States and ethanol cointoxication occurs in 34% of those cases. Cardiotoxicity is an ominous complication of cocaine and cocaethylene overdose for which no specific antidote exists. Because infusion of lipid emulsion (Intralipid) can treat lipophilic local anesthetic toxicity and cocaine is an amphipathic local anesthetic, the authors tested whether lipid emulsion could attenuate cocaine cardiotoxicity in vivo [21]. The effects of lipid emulsion were compared with the metabolically inert sulfobutylether-β-cyclodextrin (SBE-β-CD; Captisol) in an isolated heart model of cocaine and cocaethylene toxicity to determine if capture alone could exert similar benefit as lipid emulsion, which exhibits multimodal effects. The authors then tested if cocaine and cocaethylene, like bupivacaine, inhibit lipid-based metabolism in isolated cardiac mitochondria.

For whole animal experiments, Sprague-Dawley rats were anesthetized, instrumented, and pre-treated with lipid emulsion followed by a continuous infusion of cocaine to assess time of onset of cocaine toxicity. For ex vivo experiments, rat hearts were placed onto a nonrecirculating Langendorff system perfused with Krebs-Henseleit solution. Heart rate, left ventricle maximum developed pressure (LVdevP), left ventricle diastolic pressure, maximum rate of contraction (+dP/dtmax), maximum rate of relaxation (-dP/ dtmax), rate-pressure product (RPP=heart rate×LVdevP), and line pressure were monitored continuously during the experiment. A dose response to cocaine (10, 30, 50, and 100 μmol/L) and cocaethylene (10, 30, and 50 μmol/L) was generated in the absence or presence of either 0.25% lipid emulsion or SBE-β-CD. Substrate-specific rates of oxygen consumption were measured in interfibrillar cardiac mitochondria in the presence of cocaine, cocaethylene, ecgonine, and benzoylecgonine.

Treatment with lipid emulsion delayed onset of hypotension (140 seconds vs. 279 seconds; p = 0.008) and asystole (369 seconds vs. 607 seconds; p = 0.02) in whole animals. Cocaine and cocaethylene induced dosedependent decreases in RPP, +dP/dtmax, and -dP/dtmax abs (p<0.0001) in Langendorff hearts; line pressure was increased by cocaine and cocaethylene infusion, but not altered by treatment. Lipid emulsion attenuated cocaineand cocaethylene-induced cardiac depression. SBE-β-CD alone evoked a mild cardio depressant effect (p<0.0001) but attenuated further cocaine- and cocaethylene-induced decrements in cardiac contractility at high concentrations of drug (100 μmol/L; p<0.001). Finally, both cocaine and cocaethylene, but not ecgonine and benzoylecgonine, inhibited lipid-dependent mitochondrial respiration by blocking carnitine exchange (p<0.05).

A commercially available lipid emulsion was able to delay progression of cocaine cardiac toxicity in vivo. Further, it improved acute cocaine- and cocaethylene-induced cardiac toxicity in rat isolated heart while SBE-β-CD was effective only at the highest cocaine concentration. Further, both cocaine and cocaethylene inhibited lipid-dependent mitochondrial respiration. Collectively, this suggests that scavenging-independent effects of lipid emulsion may contribute to reversal of acute cocaine and cocaethylene cardiotoxicity, and the beneficial effects may involve mitochondrial lipid processing [21].

We hypothesized that acute lipid-induced insulin resistance would be attenuated in high-oxidative muscle of lean trained (LT) endurance athletes due to their enhanced metabolic flexibility and mitochondrial capacity [22]. Lean sedentary (LS), obese sedentary (OS), and LT participants completed two hyperinsulinemic euglycemic clamp studies with and without (glycerol control) the coinfusion of Intralipid. Metabolic flexibility was measured by indirect calorimetry as the oxidation of fatty acids and glucose during fasted and insulin-stimulated conditions, the latter with and without lipid oversupply. Muscle biopsies were obtained for mitochondrial and insulin-signaling studies. During hyperinsulinemia without lipid, glucose infusion rate (GIR) was lowest in OS due to lower rates of nonoxidative glucose disposal (NOGD), whereas state 4 respiration was increased in all groups. Lipid infusion reduced GIR similarly in all subjects and reduced state 4 respiration. However, in LT subjects, fat oxidation was higher with lipid oversupply, and although glucose oxidation was reduced, NOGD was better preserved compared with LS and OS subjects. Mitochondrial performance was positively associated with better NOGD and insulin sensitivity in both conditions. We conclude that enhanced mitochondrial performance with exercise is related to better metabolic flexibility and insulin sensitivity in response to lipid overload [22].

Conclusion

Two case reports of myoclonus of legs post spinal anesthesia treated successfully by IV lipid emulsion are first described in the medical literature.

A review of cases of myoclonus post regional anesthesia (spinal or epidural) are discussed with the hypothesis that the Lipid Emulsion effects are on the mitochondria and the intracellular calcium.

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Supporting Links

23. https://www.youtube.com/watch?v=dXdJkvX-jlo&feature=youtu.be

24. https://www.youtube.com/watch?v=W9QbSiV3pxQ&app=desktop

https://www.youtube.com/watch?v=7DIu9gpkCuo&feature=youtu.be
