Andrew R. Wolf

Impaired fatty acid oxidation in propofol infusion syndrome

Propofol infusion syndrome is a rare but frequently fatal complication in critically ill children given long-term propofol infusions. We describe a child who developed all the clinical features of propofol infusion syndrome and was treated successfully with haemofiltration. Biochemical analysis before haemofiltration showed a large rise in plasma concentrations of malonylcarnitine (3.3 micromol/L) and C5-acylcarnitine (8.4 micromol/L), which returned to normal after recovery. Abnormalities are consistent with specific disruption of fatty-acid oxidation caused by impaired entry of long-chain acylcarnitine esters into the mitochondria and failure of the mitochondrial respiratory chain at complex 11.

Current United Kingdom sedation practice in pediatric intensive care.

Background:  The aim of this study was to investigate the current practice of sedation, analgesia, and neuromuscular blockade in critically ill children on pediatric intensive care units (PICUs) in the UK and identify areas that merit further study.

Pharmacokinetics of Propofol Infusions in Critically Ill Neonates, Infants, and Children in an Intensive Care Unit

Background Propofol is a commonly used anesthetic induction agent in pediatric anesthesia that, until recently, was used with caution as an intravenous infusion agent for sedation in pediatric intensive care. Few data have described propofol kinetics in critically ill children. Methods Twenty-one critically ill ventilated children aged 1 week to 12 yr were sedated with 4–6 mg · kg−1 · h−1 of 2% propofol for up to 28 h, combined with a constant morphine infusion. Whole blood concentration of propofol was measured at steady state and for 24 h after infusion using high-performance liquid chromatography. Results A propofol infusion rate of 4 mg · kg−1 · h−1 achieved adequate sedation scores in 17 of 20 patients. In 2 patients the dose was reduced because of hypotension, and 1 patient was withdrawn from the study because of a increasing metabolic acidosis. Mixed-effects population models were fitted to the blood propofol concentration data. The pharmacokinetics were best described by a three-compartment model. Weight was a significant covariate for all structural model parameters; Cl, Q2, Q3, V1, and V2 were proportional to weight. Estimates for these parameters were 30.2, 16.0, and 13.3 ml · kg−1 · min−1 and 0.584 and 1.36 l/kg, respectively. The volume of the remaining peripheral compartment, V3, had a constant component (103 l) plus an additional weight-related component (5.67 l/kg). Values for Cl were reduced (typically by 26%) in children who had undergone cardiac surgery. Conclusions Propofol kinetics are altered in very small babies and in children recovering from cardiac surgery. Increased peripheral distribution volume and reduced metabolic clearance following surgery causes prolonged elimination.

Modifying infant stress responses to major surgery: spinal vs extradural vs opioid analgesia

Twenty‐six infants due to undergo major abdominal or thoracic surgery under general anaesthesia were randomized to receive additional analgesia with group A) spinal/epidural analgesia; B) epidural analgesia or C) opioid analgesia with fentanyl. We wished to determine if spinal analgesia followed by epidural analgesia might result in more complete control of cardiovascular or stress responses than the other two treatment groups. Heart rate and blood pressure were recorded at five min intervals throughout surgery. Blood samples were taken for measurement of catecholamines and whole blood sugar on induction, 45 min after skin incision and at the end of surgery. Heart rate rose significantly at the start of surgery in groups B and C but not group A. Systolic blood pressures were higher in group C compared to A and B. The rise in plasma glucose concentrations was significantly different between the groups in the order C>B>A (P<0·05). A similar trend was seen in the plasma adrenaline and noradrenaline concentrations but this failed to achieve significance due to the limited sample size.

The place of premedication in pediatric practice.

Behind the multiple arguments for and against the use of premedication, sedative drugs in children is a noble principle that of minimizing psychological trauma related to anesthesia and surgery. However, several confounding factors make it very difficult to reach didactic evidence‐based conclusions. One of the key confounding issues is that the nature of expectations and responses for both parent and child vary greatly in different environments around the world. Studies applicable to one culture and to one hospital system (albeit multicultural) may not apply elsewhere. Moreover, the study of hospital‐related distress begins at the start of the patient’s journey and ends long after hospital discharge; it cannot be focused completely on just the moment of anesthetic induction. Taking an example from actual practice experience, the trauma caused by the actual giving of a premedication to a child who absolutely does not want it and may struggle may not be recorded in a study but could form a significant component of overall effect and later psychological pathology. Clearly, attitudes by health professionals and parents to the practice of routine pediatric premedication, vary considerably, often provoking strong opinions. In this pro–con article we highlight two very different approaches to premedication. It is hoped that this helps the reader to critically re‐evaluate a practice, which was universal historically and now in many centers is more selective.

Propofol infusion in children: when does an anesthetic tool become an intensive care liability?

In the past decade, propofol has become the most popular intravenous drug for induction and maintenance of anesthesia in children, but few consider it appropriate for use as a longer-term sedative agent in the Pediatric Intensive Care Unit (PICU) because of continuing reports of deaths and life-threatening complications that are characterized by metabolic acidosis, rhabdomyolysis, cardiac and renal failure (propofol infusion syndrome) (1–6). However, despite this, propofol continues to be used by some units outside its product licence. This practice probably reflects the lack of effective alternative sedatives (7). Events came to a head in 2001 when a randomized controlled trial was conducted in the USA comparing the use of intravenous propofol (1 and 2%) with conventional sedation using multiple other agents. The observed death rate in the propofol groups was higher than that in the control group (21 of 222 vs four of 105) (8). This study remains unpublished, and much detail remains uncertain, so interpretation of the data is difficult; but after reviewing the data several national advisory bodies on drug safety issued warnings effectively forbidding the use of propofol for intensive care sedation in children. At present, certainly within the UK, few clinicians would consider it appropriate to use propofol for long-term sedation in PICU. However, there is also evidence that propofol infusion syndrome is not exclusive to PICU: it can occur in adults (9–11) and may develop within hours if excessive infusion rates are used (12). Despite the acceptance of propofol infusion syndrome as an established clinical entity, and the warnings from regulatory bodies, there remains variation in clinical practice. Some PICUs continue to use the drug routinely as a short-term extension of anesthesia after surgery, others use the drug for procedural sedation [a use for which it seems particularly suited (12)], and reports describing the use of propofol as a long-term sedative agent in PICU have continued up to the end of 2002 (13,14). Meanwhile, many units have chosen to completely withdraw this drug from PICU use. Finding the underlying cause of propofol infusion syndrome and establishing limits within which the drug might be used safely would allow more rational prescribing of a very useful drug, and avoid the current paradox which makes using propofol infusion acceptable in the operating room but unacceptable once the patient arrives on the ICU. This issue of Pediatric Anesthesia contains a case report (16) in which propofol given postoperatively at a very high infusion rate to an otherwise healthy 5-month-old child resulted in the usual features of propofol infusion syndrome . Previous papers from both animals (17) and human beings (4–6) have described impairment of fatty acid oxidation in the mitochondria associated with propofol. The authors tested this hypothesis by measuring the acyl-carnitine profile of plasma stored at the time of acute illness. The biochemical profile was not identical to the previous report by Wolf and colleagues, but it did demonstrate failure of the mitochondrial respirCorrespondence to: Prof. Andrew R. Wolf, Paediatric Intensive Care Unit, Bristol Children’s Hospital, Upper Maudlin St., University of Bristol, Bristol, UK. Pediatric Anesthesia 2004 14: 435–438

Should we reconsider awake neonatal intubation? A review of the evidence and treatment strategies

Tracheal intubation is a frequent and routine neonatal procedure that is often performed without anaesthesia or premedication (1). The concept of painful or uncomfortable procedures performed in a child without analgesia or anaesthesia provokes strong opinions in both the medical and nonmedical literature (2±6). While this issue remains highly emotive, what evidence is there to show that awake intubation in premature and term neonates is detrimental in terms of physical and physiological consequences? Is there evidence to show that neonates have the ability to perceive the noxious stimulus of laryngoscopy as pain? If this evidence exists, what strategies are available to ensure safety and avoid the potential unwanted physical and physiological effects of awake intubation?

The outcome of children requiring admission to an intensive care unit following bone marrow transplantation

We report the results of a retrospective study of the role of intensive care unit (ICU) admission in the management of 367 children who underwent bone marrow transplantation (BMT) at a tertiary referral institution. 39 patients (11%) required 44 ICU admissions for a median of 6 d. 70% received marrow from unrelated donors, half of which were mismatched; 80% had leukaemia and two‐thirds were considered high‐risk transplants. Respiratory failure was the major reason for admission to ICU. 75% of admissions required mechanical ventilation (for a median of 5 d) and 20 patients had lung injury as defined by the criteria of the Seattle group. None of 11 patients with proven viral pneumonitis survived (P = 0.06) and only one of 20 patients with lung injury survived (P < 0.01). Six of seven patients with a primary neurological problem survived (P < 0.001); these appear to represent a good outcome group. Age, the presence of graft‐versus‐host disease, the use of inotropes, isolated renal or hepatic impairment, and paediatric risk of mortality (PRISM) score were not predictive of outcome. In total, 12 patients (27% of admissions) survived and were discharged from hospital 30 d or more after admission and eight (18%) survived >6 months. ICU admission can be beneficial to selected children post‐BMT but it may be less useful in proven viral pneumonitis. Where mechanical ventilation is required, the duration of this support should be limited unless there is rapid improvement.

Evidence for Cardiovascular Autonomic Dysfunction in Neonates With Coarctation of the Aorta

Background— Coarctation of the aorta (CoA) is associated with hypertension and abnormalities of blood pressure control, which persist after late repair. Assumptions that neonatal repair would prevent development of blood pressure abnormalities have not been supported by recent data. We hypothesized that early pathological adjustment of autonomic cardiovascular function may already be established in the neonate with coarctation. Methods and Results— We studied 8 otherwise well neonates with simple CoA and compared measures of spontaneous baroreflex sensitivity, heart rate variability, and blood pressure variability with 13 healthy newborn babies. Spontaneous baroreflex sensitivity was calculated with sequence methodology from an ECG, and noninvasive blood pressure was recorded with a Portapres. Heart rate variability was determined with time- and frequency-domain measures. Blood pressure variability was measured in the frequency domain. In comparison with normal controls, neonates with CoA had raised blood pressure (78.9±3.8 versus 67.1±2.1 mm Hg), depressed baroreflex sensitivity (8.7±1.5 versus 13.8±1.1 ms/mm Hg), reduced heart rate variability (total power 16.5±3.1 versus 31.5±2.2 ms2), and an increase in the high-frequency component of blood pressure variability (3.1±0.3 versus 2.2±0. 2 mm Hg2). This is not the pattern expected if neonates with CoA simply had subclinical cardiac failure. Conclusions— These data suggest that infants with CoA already show signs of pathological adjustment of autonomic cardiovascular homeostasis. Further longitudinal studies are required to determine whether these alterations play a role in the increased risk of late hypertension in these patients.

Efficacy, safety, and pharmacokinetics of levobupivacaine with and without fentanyl after continuous epidural infusion in children a multicenter trial

Background Levobupivacaine, the levo-enantiomer of bupivacaine, is as potent as bupivacaine but less toxic. Therefore, the authors investigated the efficacy, safety, and pharmacokinetics of perioperative epidural levobupivacaine with and without fentanyl in children. Methods After Research Ethics Board approval and informed written consent, 120 healthy children aged 6 months to 12 yr who were scheduled to undergo urologic or abdominal surgery were randomized in a double-blinded and concealed manner to receive one of four epidural solutions as a continuous infusion for 24 h: 0.125% levobupivacaine; 0.0625% levobupivacaine; 1 &mgr;g/ml fentanyl; or the combination, 0.0625 levobupivacaine and 1 &mgr;g/ml fentanyl. After induction of anesthesia and tracheal intubation, a lumbar epidural catheter was sited, a loading dose was administered (0.75 ml/kg levobupivacaine, 0.175%), and the epidural infusion was commenced. The primary endpoint was the need for rescue analgesia (morphine) in the first 10 h after surgery. Pain, motor strength, and side effects were recorded for 24 h. Venous blood was collected from 18 children to determine the plasma concentrations of levobupivacaine and/or fentanyl before and 2, 4, 8, 16, 24, and 26 or 30 h after the start of the epidural infusion. Results Of the 114 children who were analyzed for intention to treat, a similar number of children in each group reached the 10-h mark. The time to the first dose of morphine in the first 10 h was less in the plain fentanyl group (P < 0.044). All other effects were similar among the four groups. The plasma concentration of levobupivacaine increased during the infusion period, reaching a maximum of 0.76 ± 0.11 &mgr;g/ml in the 0.125% group and 0.48 ± 0.12 &mgr;g/ml in the 0.0625% group by 24 h. The plasma concentration of fentanyl also increased steadily, reaching a maximum concentration of 0.37 ± 0.11 ng/ml by 24 h. Conclusion We conclude that 0.0625% levobupivacaine without fentanyl is an effective perioperative epidural solution in children when infused at a rate of 0.3 ml · kg−1 · h−1. The plasma concentrations of 0.125% and 0.0625% levobupivacaine and fentanyl (1 &mgr;g/ml) at the end of a 24-h infusion are low.