Journal Year in Review

Regional Anesthesia & Pain Medicine

Dr. HaysBy Stephen Robert Hays, MD, FAAP
Associate Professor, Anesthesiology & Pediatrics
Vanderbilt University School of Medicine, Nashville, TN
Director, Pediatric Pain Services
Monroe Carell, Jr. Children's Hospital at Vanderbilt, Nashville, TN

Welcome to the inaugural Society for Pediatric Pain Medicine Newsletter, and to what we hope will be a regular feature: Journal Year in Review. Given Society interest in pediatric pain medicine across numerous disciplines, we thought it might be useful to highlight articles of potential interest from various journals that might not regularly cross the desk of many pediatric anesthesiologists. In this issue we will look back at the past year in Regional Anesthesia & Pain Medicine, with similar surveys to come in future issues. If you have suggestions for specific articles, other journals, or areas of focus to be reviewed, please let us know!

Triangulating the Caudal Hiatus: Another Adult Anatomic Tradition Bites Pediatric Ultrasonographic Dust
One method of identifying the appropriate site for caudal block uses an inverted equilateral triangle extending inferiorly from the two posterior superior iliac spines, with the apex of the triangle indicating the caudal hiatus: this method has been anatomically validated for adults, in whom sacral cornua may be difficult to appreciate. One of the year’s only pediatric articles in Regional Anesthesia & Pain Medicine suggests this is not an anatomically valid technique in children.

Investigators in South Korea compared predicted location of the caudal hiatus using the equilateral triangle method with actual location using ultrasonography in 80 infants and children, ages 0.5-72 months, undergoing inguinal hernia repair under combined general anesthesia with laryngeal mask airway and regional anesthesia with caudal block. Former premature infants and children with bony abnormalities or contraindications to caudal block were to be excluded, although there were no actual exclusions or withdrawals.

Compared to the equilateral triangle method, the angle between the lines connecting the ultrasonographically verified caudal hiatus to the posterior superior iliac spines was > 60 degrees in all patients; moreover, the vertical distance between the actual hiatus and the level of the posterior superior iliac spines was less than predicted by the equilateral triangle method in all patients. In other words, the caudal hiatus always lay more cephalad than predicted by the equilateral triangle method. Performance of the equilateral triangle method inversely correlated with patient age, weight, height, and distance between the posterior superior iliac spines; the equilateral triangle method was particularly inaccurate in infants < 1 year of age, but approached validity as children approached age 72 months.

Comment: In adults, an inverted equilateral triangle extending inferiorly from the posterior superior iliac spines reasonably reliably identifies the caudal hiatus; this method appears progressively inaccurate in children under 6 years of age, particularly in infants < 1 year of age. Given that caudal blocks are probably performed most often precisely in such younger patients, this study will likely do little for clinical pediatric anesthesia practice, other than to remind us once again that adult anatomic guidelines do not necessarily apply to children, including in regional anesthetic techniques.

Kim MS, Han KH, Kim EM: The myth of the equiangular triangle for identification of sacral hiatus in children disproved by ultrasonography. Reg Anesth Pain Med 2013 May-Jun;38(3):243-7.

Local Anesthetic Systemic Toxicity: Ultrasound Probably Does Make Peripheral Nerve Blocks Safer
One of the feared complications of regional anesthetic techniques is local anesthetic systemic toxicity, particularly with agents such as bupivacaine: before the advent of lipid rescue, prolonged resuscitation potentially including extracorporeal support was the only recourse for management, often resulting in death or significant disability. Children, especially neonates, are thought to be a greater risk for local anesthetic systemic toxicity. Ultrasound guidance in regional anesthetic techniques increases success and decreases complications, and in children has been shown dramatically to reduce required volume of local anesthetic. A study from Down Under in Regional Anesthesia & Pain Medicine suggests ultrasound guidance reduces risk and perhaps severity of local anesthetic toxicity with peripheral nerve block.

Investigators in Australia queried the Australian and New Zealand Registry of Regional Anaesthesia, collecting data from 20 participating institutions over a 5-year period from 2007-2012. Various demographic and procedural variables were captured; peripheral nerve blocks were identified as having been done with or without ultrasound; local anesthetic toxicity was classified as minor (agitation), major (loss of consciousness, seizure), or cardiac (cardiac arrest). Multivariate analyses including propensity scores for various patient and institutional factors were employed.

In all, 20,021 patients underwent 25,336 peripheral nerve blocks. There were 22 episodes of local anesthetic systemic toxicity (13 minor, 8 major, 1 cardiac arrest), with an overall incidence of 0.87 per 1000 blocks; the cardiac arrest occurred in the non-ultrasound group following a paravertebral block with subsequent successful lipid rescue. Toxicity occurred in 2.1 per 1000 blocks performed without ultrasound versus 0.59 per 1000 blocks performed with ultrasound, a statistically significant difference (P = 0.004; Odds Ratio 0.28). Toxicity was noted with ropivacaine, by far the most commonly used local anesthetic, and with lidocaine, the second most commonly used agent; interestingly, no toxicity of any severity occurred with bupivacaine. Toxicity was also associated with dose of local anesthetic (higher dose), agent used (lidocaine versus ropivacaine), and type of block (paravertebral or upper extremity versus lower extremity).

Comment: Although this retrospective cohort analysis of prospectively entered registry data cannot prove causality, the associations noted are plausible and makes sense. Ultrasound guidance for peripheral nerve block is associated with reduced risk, and perhaps reduced severity, of local anesthetic systemic toxicity. Unsurprisingly, toxicity is associated with increased dose of agent administered, as well as with paravertebral and upper extremity blocks, likely secondary to increased vascularity of these areas. The association of toxicity with lidocaine versus ropivacaine is something of a surprise: most anesthesiologists would probably consider lidocaine the safer agent. Although these data represent experience with peripheral nerve blocks in adults, there is no reason to believe they would not apply to other regional anesthetic techniques, and to children.

Barrington MJ, Kluger R: Ultrasound guidance reduces the risk of local anesthetic systemic toxicity following peripheral nerve blockade. Reg Anesth Pain Med 2013 Jul-Aug;38(4):289-97.

Regional Anesthesia and Long-Term Oncologic Survival: Can Epidurals Help Cure Cancer?
Immunosuppression adversely affects long term survival in patients with malignancy. The perioperative neuroendocrine stress response is potently immunosuppressive; moreover, blood product transfusion and systemic opioid administration both suppress immune function, and demonstrate dose-dependent associations with decreased oncologic survival. Regional anesthetic techniques blunt perioperative stress, may reduce transfusion requirement, and usually allow reduction in systemic opioid: might perioperative regional anesthesia improve long term survival in cancer patients? A recent study in Regional Anesthesia & Pain Medicine suggests it might.

Investigators at a single institution in France retrospectively evaluated their experience with adults undergoing surgical resection of laryngeal or hypopharyngeal cancer over almost a quarter-century between 1984 and 2008: 111 patients received combined general endotracheal anesthesia with perioperative cervical epidural, while 160 patients received general anesthesia without cervical epidural or other regional anesthetic technique. Cervical epidurals were placed before induction of general anesthesia, dosed with local anesthetic with or without opioid intraoperatively, and used with opioid in some patients for postoperative analgesia; patients without epidurals received intraoperative opioid at anesthesia provider discretion, with postoperative morphine per institutional routine. Propensity matching generated 65 patient pairs with and without cervical epidural for analysis.

Percentage of patients requiring postoperative opioid was significantly lower in the cervical epidural group than in the non-epidural group (7.8% versus 80%, P < 0.01); percentage of patients receiving perioperative blood product was also lower in the epidural group, although this difference fell just short of statistical significance (10.8% versus 23.1%, P = 0.06). Five-year cancer-free survival was greater in the epidural group at 5 years (68% versus 37%, adjusted Hazard Ratio 0.49, P = 0.04), as was overall survival at 5 years (59% versus 41%, adjusted Hazard Ratio 0.61, P = 0.03).

Comment: A fascinating study with tantalizing results. Use of perioperative cervical epidural for such procedures is laudable, and the total number of patients is impressive for a relatively uncommon technique. That perioperative epidural anesthesia should reduce postoperative opioid requirement is unsurprising; that epidurals should reduce perioperative transfusion requirement is somewhat less intuitive, but has been described in numerous settings and noted in meta-analyses of available studies. The observed association between perioperative cervical epidural and improved long term oncologic outcome is biologically plausible: reductions in perioperative stress, transfusion requirement, and systemic opioid, each of which can be achieved with perioperative regional anesthesia, should blunt perioperative immunosuppression, potentially improving survival. The idea that regional anesthesia can help cure cancer deserves careful consideration in perioperative planning for oncology patients, and study in pediatric populations.

Merquiol F, Montelimard AS, Nourissat A, Molliex S, Zufferey PJ: Cervical epidural anesthesia is associated with increased cancer-free survival in laryngeal and hypopharyngeal cancer surgery: a retrospective propensity-matched analysis. Reg Anesth Pain Med 2013 Sep-Oct;38(5):398-402.

When Opioid Doesn’t Help: Defining a Centralized Pain Phenotype
Patients with chronic non-oncologic pain represent a challenging population. Although few data support efficacy of chronic opioid in most patients with chronic non-oncologic pain, opioids are increasingly prescribed to such patients, often with little apparent therapeutic benefit. Many patients with chronic non-oncologic pain continue to report severe pain despite opioid: identifying which patients are most likely to do so, with an understanding of the pain phenotype they represent, could be of potential benefit in tailoring appropriate therapy. A study in the current issue of Regional Anesthesia & Pain Medicine identifies a cohort of patients with ongoing severe non-oncologic pain despite opioid, and describes these patients as representing a centralized pain phenotype analogous to fibromyalgia.

Investigators prospectively evaluated 1208 adults with non-oncologic pain presenting for initial evaluation to the University of Michigan Back and Pain Center with a variety of self-report instruments. Pain severity was assessed with the Brief Pain Inventory; opioid use was identified with an extensive checklist of generic and brand names. Characteristics of subjective pain experience were evaluated with the American College of Rheumatology survey criteria for fibromyalgia (2011 criteria not requiring tender point examination), Widespread Pain Index and Michigan Body Map (number of painful body areas), Symptom Severity scale (comorbid symptomatology), PainDETECT (neuropathic pain), Hospital Anxiety and Depression Scale, and PROMIS Function Short Form (functional status).

Fully 582 of 1208 (48.2%) of patients with chronic non-oncologic pain reported currently taking at least one opioid and provided sufficient data for analysis; 49.1% of these patients continued to report severe pain ≥ 7/10 despite opioid. Although 40.8% of patients taking opioid met American College of Rheumatology survey criteria for fibromyalgia, only 3.2% of these patients were given a primary diagnosis of fibromyalgia by their treating physician; secondary diagnoses were not queried. In regression model multivariate analyses, increased pain intensity in patients taking opioid was associated with non-white ethnicity, non-married social status, non-college-graduate education, higher fibromyalgia survey scores, greater neuropathic pain symptomatology, and depression. Interestingly, anxiety and functional status were not independently associated with pain severity.

Comment: This retrospective adult cohort study validates a common observation in chronic pain practice: many patients with chronic non-oncologic pain are precisely those patients who continue to report ongoing severe pain even with opioid. These patients likely represent a centralized pain phenotype analogous to fibromyalgia, in which pharmacologic intervention including opioid is often of little therapeutic benefit. The demographic characteristics and pain descriptors noted may aid in identification of such patients, encouraging emphasis on functional recovery through physical rehabilitation and mental health care. The incidence and nature of this centralized pain phenotype in children is largely unknown, although recurrent abdominal pain syndrome and other pediatric functional pain diagnoses likely represent variants.

Wasserman RA, Brummett CM, Goesling J, Tsodikov A, Hassett AL: Characteristics of chronic pain patients who take opioids and persistently report high pain intensity. Reg Anesth Pain Med 2014 Jan-Feb;39(1):13-7.

Nitrous Oxide and Preemptive Analgesia: Not for Immediate Postoperative Pain
Nitrous oxide is an N-methyl-D-aspartate (NMDA) antagonist with potent immunomodulatory effects. Other NMDA antagonists (ketamine) and anti-inflammatory agents (non-steroidal anti-inflammatory drugs) demonstrate analgesic efficacy with varying degrees of opioid-sparing benefit in the perioperative setting, but the effect of nitrous oxide on postoperative pain remains controversial. Various studies have suggested either increased or decreased acute postoperative pain following anesthesia using nitrous oxide, whereas the recent Evaluation of Nitrous Oxide in the Gas Mixture for Anaesthesia (ENIGMA) trial indicated decreased incidence of chronic (≥ 3 months) postoperative pain if nitrous oxide was used. A study in the current issue of Regional Anesthesia & Pain Medicine suggests intraoperative nitrous oxide has little effect on immediate postoperative pain.

Investigators in the United States and Austria conducted a post-hoc analysis of patients enrolled in the previously published Vitamins In Nitrous Oxide (VINO) Trial assessing effect of intraoperative nitrous oxide with or without concomitant vitamin B infusion on homocysteine levels and cardiovascular events in adults with two methylenetetrahydrofolate reductase polymorphisms undergoing non-cardiac surgery (in that study, nitrous oxide induced an increase in homocysteine levels blunted with concomitant vitamin B infusion, but neither homocysteine levels nor polymorphisms had an effect on cardiac troponin levels). In the current study, primary outcome was postoperative opioid requirement in recovery; secondary outcomes included intraoperative opioid consumption, patient-reported pain scores in recovery, and prevalence of moderate-serve pain in recovery. Pain after discharge from recovery was not assessed.

Of the original VINO cohort (500 patients randomized to intraoperative nitrous oxide with or without concomitant vitamin B infusion, 125 non-randomized control patients not receiving nitrous oxide), 442 patients (353 receiving nitrous oxide, 89 not receiving nitrous oxide) were evaluated after excluding those with factors potentially influencing postoperative pain including perioperative regional anesthesia. Time in recovery was not significantly different between patients receiving and not receiving nitrous oxide (131 minutes versus 134 minutes, P = 0.49). Postoperative opioid requirement in recovery, intraoperative opioid consumption, maximum pain score in recovery, and prevalence of moderate-severe pain in recovery were all similar in patients receiving or not receiving nitrous oxide. Patients reporting frequent preoperative opioid use had higher opioid consumption than those who did not report such use, but again demonstrated no differences in outcomes based on exposure to nitrous oxide.

Comment: Adult patients undergoing non-cardiac surgery who received nitrous oxide intraoperatively had similar opioid requirements and pain scores in the first 2 postoperative hours compared to patients not receiving nitrous oxide. We still do not know whether nitrous oxide increases, decreases, or has no impact on acute postoperative pain beyond the recovery room. Recent data suggest nitrous oxide may decrease incidence of chronic postoperative pain, but the implications of this observation for clinical practice are similarly unclear. Despite over two centuries of use, the effects of nitrous oxide on postoperative pain, particularly in children, remain an ENIGMA.

Duma A, Helsten D, Brown F, Bottros MM, Nagele P: The effect of nitrous oxide anesthesia on early postoperative opioid consumption and pain. Reg Anesth Pain Med 2014 Jan-Feb;39(1):31-6.

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