Davinia E. Withington

A case of propofol toxicity: further evidence for a causal mechanism

Summary A 5‐month‐old boy required sedation after a cleft lip repair. He was sedated with propofol and intermittent fentanyl, requiring escalating doses over the subsequent 48u2003h. On the second post‐operative day he developed a metabolic acidosis followed by multiple cardiac dysrhythmias, hepatic and renal failure. Propofol was stopped. His multisystem organ failure gradually resolved after initiation of charcoal haemoperfusion. Further investigation demonstrated an abnormality in acylcarnitine metabolism, similar to that found in one previous case report.

Vecuronium pharmacokinetics and pharmacodynamics during hypothermic cardiopulmonary bypass in infants and children.

Purpose: To determine the effect of moderate and deep hypothermic cardiopulmonary bypass (CPB) on the pharmacokinetic and pharmacodynamic behaviour of vecuronium in infants and children.Methods: We studied 12 patients undergoing surgery for congenital heart disease under narcotic-nitrous oxide anesthesia. Neuromuscular blockade was maintained constant (TI 4–10% by Datex electromyograph) by adjusting a vecuronium infusion. Plasma vecuronium concentrations (Cpss) were analysed by HPLC to describe a pseudosteadystate during each of the pre-CPB, CPB and post-CPB phases. Paired arterial blood samples were taken 20 min apart after at least 20 min of constant infusion.Results: Nine cases were analysed, mean age 20 mo, mean weight 9 kg. Three patients had deep and six moderate hypothermia. In the pre-CPB phase Cpss fell into two groups (mean±SD: 330±42 ng·ml−1; 127±27 ng·ml−1P<0.001); similarly the clearances showed a bimodal distribution (mean±SD; 5.08±0.94; 11.51±0.2 ml·min−1·kg−1P<0.001), although in different patients. During CPB this bimodal distribution disappeared. Vecuronium infusion rate (VIR) decreased by 84% and 92% from pre-CPB to CPB phase in deep and moderate hypothermia groups respectively (P<0.05), paralleled by decreases in Cpss of 36% (P>0.05) and 52% (P<0.05).Conclusion: Changes in vecuronium requirements and plasma concentrations during CPB demonstrate that vecuronium pharmacokinetics and pharmacodynamics are both affected by hypothermic CPB in infants. The finding of bimodal distributions for plasma vecuronium and vecuronium clearance highlights the need for individual monitoring of neuromuscular blockade in this age group.RésuméObjectif: Déterminer l’effet d’une circulation extracorporelle (CEC) avec hypothermie modérée ou profonde sur les paramètres pharmacocinétiques et pharmacodynamiques du vécuronium chez des nourrissons et des enfants.Méthode: Nous avons étudié 12 patients opérés pour cardiopathie congénitale sous anesthésie avec un mélange de narcotique et de protoxyde d’azote. Le blocage neuromusculaire a été maintenu constant (TI 4–10% avec un électromyographe Datex) en ajustant une perfusion de vécuronium. Les concentrations plasmatiques de vécuronium (Cpss) ont été analysées par chromatographie liquide haute performance (CLHP) afin de définir l’état pseudo-équilibre pendant chacune des étapes pré-CEC, CEC et post-CEC. Des échantillons appariés de sang artériel ont été prélevés à intervalles de 20 min, après au moins 20 min de perfusion constante.Résultats: Neuf cas ont été analysés, âgés de 20 ms et pesant 9 kg en moyenne. Trois patients avaient une hypothermie profonde et six, une modérée. Pendant la pré-CEC, les Cpss se séparent en deux groupes (moyenne±écart type: 330±42 ng·ml−1; 127±27 ng·ml−1P<0,001); les clairances ont affiché une distribution bimodale (moyenne ± écart type: 5,08±0,94; 11,51±0,2 ml·min−1·kg−1P<0,001), chez différents patients cependant. Pendant la CEC, cette distribution bimodale a disparu. La vitesse de perfusion du vécuronium (VPR) a diminué de 84% et 92%, comparée à celle de la pré-CEC chez les patients avec hypothermie profonde et modérée, respectivement (P<0,05), parallèlement à une baisse des Cpss de 36% (P>0,05) et de 52% (P<0,05).Conclusion: Les besoins différents de vécuronium et les changements de concentrations plasmatiques pendant la CEC montrent que la pharmacocinétique et la pharmacodynamie du vécuronium sont influencées par une CEC hypothermique chez l’enfant. La découverte de distributions bimodales de vécuronium plasmatique et de clairance du vécuronium, souligne la nécessité d’un monitorage du blocage neuromusculaire chez les patients de cet âge.

Cisatracurium pharmacokinetics and pharmacodynamics during hypothermic cardiopulmonary bypass in infants and children.

Background:u2002 Hypothermia potentiates neuromuscular blockade in adults during cardiopulmonary bypass (CPB) but the pediatric literature is sparse. Temperature‐dependent Hoffman degradation of cisatracurium may allow reduction in infusion rate (IR) during hypothermia. The effect of hypothermic CPB on the pharmacokinetics (PK) and pharmacodynamics (PD) of cisatracurium has not been described in children.

Allergy, anaphylaxis and anaesthesia

The average anaesthetist is likely at most, to see one severe allergic reaction a year; many may see only one in their entire professional careers. A dearth of clinical exposure is parallelled by lack of familiarity with immunological terminology. However, given the rapidity with which a life-threatening situation can occur, the mechanisms, therapy and investigation of allergic responses should be familiar to every anaesthetist. Terminology An adverse drug reaction is any drug response which is not of therapeutic, prophylactic or diagnostic benefit to the patient, i Type A reactions are dose-related, predictable from pharmacological effects and common; Type B are uncommon, unpredictable, often worse with repeated exposure and unrelated to the normal pharmacological response. This latter group of allergic responses are subdivided into anaphylactic and anaphylactoid reactions, but are clinically indistinguishable. Anaphylactic reactions are immunologicaUy mediated, usually by lgE (Type I hypersensitivity), whereas anaphylactoid reactions may be produced by direct release of vasoaetive substances or by complement activation via the alternative pathway. 2 Allergy is a hypersensitive state caused by exposure to a specific antigen, re-exposure to which will produce an anaphylactic reaction.

Histamine release during cardiopulmonary bypass in neonates and infants

PurposeHistamine release has been previously documented in adults and children during cardiopulmonary bypass (CPB). It has not been studied in neonates nor during deep hypothermic circulatory arrest (DHCA). Histamine effects could explain many penoperative complications of congenital cardiac surgery such as dysrhythmias and massive oedema. Therefore, documentation of histamine release in the penoperative period is of clinical importance. The source of histamine can be determined by measurement of tryptase which is released with histamine from mast cells but not basophils.MethodsBlood samples for histamine and tryptase were taken before and after specific events eg. cross-damp removal, during anaesthesia and CPB in 14 infants and seven neonates undergoing complex congenital heart repairs and were analysed by commercial radiommunoassays. Haemodynamic variables and pre and post-op weights were recorded to look for correlation between pathophysiologcal events and histamine release.ResultsHistamine concentration decreased at the start of bypass (0.69 to 0.38 ng · ml−1 at five minutes, (P < .005). There were no changes associated with DHCA and a small rise with reventilation (P < 0.02). Histamine concentration was lower in neonates than in infants (P < 0.05) during CPB. Plasma histamine and tryptase concentrations did not correlate, suggesting histamine release was from basophils and not from mast celts. Haemodynamic variables did not correlate with histamine concentrations.ConclusionThere was no major histamine release during CPB in infants and neonates. There was no relationship between histamine concentrations and dinical variables. Histamine released during CPB appears to come from basophils and may be a function of age.RésuméObjectifLa libération d’hrstamine a déjà été documentée chez des enfants et des adultes pendant la circulation extracorporelle (CEC). Elle n’a pas été recherchée chez les nouveau-nés ou pendant l’arret circulatore en hypothenmie profonde (ACHP). Les effets de l’histamine pourraient expliquer plusieurs des complictions postopératoires de la chirurgie des cardiopathies congénitales comme les dysrythmies et l’oedème pulmonaire massif. Il est donc important du point de vue dinique de corroborer la libération d’histamine à la période périopératoire. La source de l’histamine peut être déterminée par le dosage de la tryptase libérée avec l’histarnine par les mastocytes mais non les basophiles.MéthodesDes échantions sangums ont été prélevés pour le dosage de l’histamine et de la tryptase avant et après des événements spécifiques, per ex. le retrait du damp aortique, pendant l’anesthésie et la CEC, diez 14 enfants et sept nouveau-nés sournis des correction chinurgicales de malformation corgénitale compliquées. Les échantillons ont été analysés par dosage radioirnmunologique. Les variables hémodynarniques et les pesées pré- et postopératoires ont été enregistrées pour rechercher une corrélation entre les événements physiopathologiques et la libération d’histamine.ResultatsLa concentration d’histamine a diminué au début de la CEC de 0,69 à 0,38 ng · ml−1 à la cinquième minute (P < 0,005). Aucun changement n’a été associé à l’ACHP. Une légère augmentation est survenue avec la reprise de la ventilation (P < 0,02). Rendant la CEC, les concentrations d’histamine des enfants étaient inférieures à celles des nouveau-nés (P < 0,05). Il n’y avait pas de corrélation entre les concentrations de tryptase et d’histamine, suggérant ainsi que l’histamine était libérée à partir des basophites plutôt que des mastocytes. Les variables hérnodynamique ne corréiaient pas avec les concentrations d’histamine.ConclusionOn n’a pas noté de libération importante d’histamine pendant la CEC chez les enfants et les nouveaunés. L’histamine libérée semble provenir des basophiles et pourrait être en fonction de l’âge.

A comparison of three dose timings of methylprednisolone in infant cardiopulmonary bypass

Although commonly used in pediatric cardiopulmonary bypass (CPB) optimal dose and timing of steroid administration is unclear. We hypothesized that early administration of a commonly used dose of methylprednisolone given the evening before surgery (ultra-early) would be more effective in decreasing CPB-related inflammatory response than when given at induction of anesthesia (early) or in pump prime (standard).This was a triple-arm, parallel, active control, superiority RCT including 54 infants <2 years old who were randomised to receive 30 mg/kg methylprednisolone at one of the 3 time points. Outcomes included alveolar-arterial oxygen gradient (AaDO2) during, 24, 48 and 72 hours post-CPB, IL-6, IL-8 and reduced (GSH) to oxidized (GSSG) glutathione ratio (pre-ultrafiltration on CPB, end-CPB and 24 hours), PICU length of stay (LOS) and ventilator days. Data were analysed using descriptive statistics and a random effects regression model.The ultra-early group had higher Risk Adjusted Congenital Heart Surgery Score, lower age and longer CPB times than the other groups. No significant differences in AaDO2, IL-8, PICU LOS and ventilator days were observed between groups. Compared to the ultra-early group, the overall rise in IL-6 in the early and standard groups was lower, -27.8 pg/ml (95% CI -52.7,-2.9) and -35.3 pg/ml (95% CI -64.3,-6.34), respectively. GSH:GSSG was significantly lower in the standard group (-35.9; 95% CI -63.31,-8.5) at 24 hours post-CPB.Ultra-early administration of methylprednisolone does not improve AaDO2 post-CPB, nor diminish cytokine release. Lower GSH:GSSG in the standard group suggests less oxidative stress. However despite statistical adjustments conclusions are limited by the unbalanced randomisation of the groups.

Respiratory function in children during recovery from neuromuscular blockade

Residual neuromuscular blockade is a major risk factor for respiratory insufficiency. We examined the relationship between neuromuscular and respiratory function in 18 ASA I or II children aged 2–4 years. Lung function was measured by pneumotachography and transpulmonary pressure, neuromuscular transmission by first twitch response ratio (T1:T1) and train‐of‐four ratio (TOFR), before and at specific points in recovery from vecuronium paralysis. The tidal volume was directly related to maximal inspiratory pressure at occlusion (PIocc), P<0.001, whereas the minute ventilation (VE) was related to the respiratory drive (P0.1), P<0.001. The best predictors of minute ventilation were the P0.1 (r=0.57), and the TOFR (r=0.62). PIocc and P0.1 correlated closely (r=0.889, P=0.002) but TOFR and T1:T1 did not correlate with either. Our results show that the occlusion pressure measurements, P0.1 and PIocc, were good predictors of both VE·kg−1 and respiratory work.

Too clever by half? Can bilateral or unilateral NIRS monitoring improve neurological outcome from pediatric cardiopulmonary bypass?

Medical technologies commonly enter the marketplace without clear evidence of their efficacy or their superiority over current practice and without indepth knowledge of the secondary effects. Unlike medications, which undergo stringent Federal Drug Administration (FDA) or other national testing, new technologies are evaluated to guarantee safety and effectiveness . However, the broader definition of these terms is not ensured. A safe device will not explode and will physically do no harm . An effective device will measure (for example) what it says it will measure, but there is no guarantee that the use of the device will not lead to patient harm. The adoption of the cardiopulmonary bypass (CPB) machine was a crucial part of the development of congenital heart surgery; however, it is only in recent years that the risks have become apparent, including such repercussions as the inflammatory response. Historically, we have adopted new technologies because logically they make sense to us, because other people have used them with perceived success, and because (let us be honest) the companies have performed a good job marketing them. This is currently the case with near infrared spectroscopy (NIRS) or cerebral oximetry, which is being promoted as a means of diminishing neurological morbidity after CPB. Neurological morbidity has received increasing attention as mortality from the actual surgery and CPB has plummeted in the last two decades. Neurological problems linked to pediatric CPB were highlighted by the Boston group who were able to link them to intraoperative management (1). Other investigations have emphasized the frequency of neurologic morbidity, particularly in the neonatal population with congenital heart disease (2). Improvements in CPB technology and surgical advances have diminished some of these problems (adoption of pH stat., etc.); however, there remain a significant number of infants who experience morbidities ranging from postoperative seizures to stroke. It is therefore appropriate to investigate any technologies, which may provide the basis for a strategy to reduce the incidence of these potentially catastrophic events. Near infrared spectroscopy was originally described in the scientific literature in the late 1990s (3). It is based on science that is fully described elsewhere (4,5). Used as a trend monitor, it provides a noninvasive assessment of cerebral oxygen supply relative to demand. Currently, there exist two different machines (NIRO 300 and INVOS 5100), one of which (INVOS 5100) has FDA approval. A comparison of the two devices yielded a positive correlation of only 0.58 in absolute values; however, the correlation for changes from baseline was significantly higher at r 1⁄4 0.85 (6). Partially, as a result of this, the monitors are used only as trending devices. In the pediatric population, there has been some difficulty in validating the technology, with different studies finding varying degrees of correlation with jugular venous oxygen saturations (7–9). Animal models have demonstrated that decreases in NIRS are associated with events such as cerebral hypoxemia, anemia, and hypothermia, as well as outcomes Correspondence to: Dr Davinia Withington, Pediatric Intensive Care, C807, Montreal Children’s Hospital, 2300 Tupper Street, Montreal, Quebec, Canada H3H 1P3 (email: davinia.withington@ mcgill.ca). Pediatric Anesthesia 2006 16: 709–711 doi:10.1111/j.1460-9592.2006.01988.x

Perioperative Fluid Management

Correct management of perioperative fluids can make the difference between good and bad outcomes in pediatric anesthesia. Effective correction of preoperative fluid deficits, including those due to hemorrhage or vomiting, combined with careful maintenance and replacement of ongoing losses, will ensure that a stable child arrives in the recovery room or pediatric intensive care unit (PICU).

Extensive lower limb injuries in a child complicated by complex pain management and profound anemia

We describe a case of severe pain associated with extensive lower limb injures in a 5‐year old, complicated by profound anemia in a Jehovah’s Witness family. The study was carried out in a pediatric intensive care unit of a tertiary level university hospital. The patient was 5‐year‐old girl, with multiple open fractures and extensive soft tissue loss on her left foot and ankle due to a lawnmower injury leading to severe pain and profound anemia with management of the latter complicated by family beliefs. The interventions given were multi‐modal pain management and treatment of severe anemia with avoidance of transfusion. A drop in hemoglobin from 11.6u2003g·dl−1 at admission to a nadir of 4.3u2003g·dl−1 on day 7 was observed. Effective pain control was achieved with nurse‐ and then patient‐controlled analgesia plus adjuncts. Effective pain management and control of anxiety can be achieved by a multi‐modal approach in young children. Profound anemia was treated without transfusion and without compromise of tissue healing.