Edmund H. Jooste

Perioperative Crystalloid and Colloid Fluid Management in Children: Where Are We and How Did We Get Here?

It has been more than 50 yr since the landmark article in which Holliday and Segar (Pediatrics 1957;19:823–32) proposed the rate and composition of parenteral maintenance fluids for hospitalized children. Much of our practice of fluid administration in the perioperative period is based on this article. The glucose, electrolyte, and intravascular volume requirements of the pediatric surgical patient may be quite different than the original population described, and consequently, use of traditional hypotonic fluids proposed by Holliday and Segar may cause complications, such as hyperglycemia and hyponatremia, in the postoperative surgical patient. There is significant controversy regarding the choice of isotonic versus hypotonic fluids in the postoperative period. We discuss the origins of perioperative fluid management in children, review the current options for crystalloid fluid management, and present information on colloid use in pediatric patients.

Perioperative Use of Dexmedetomidine Is Associated With Decreased Incidence of Ventricular and Supraventricular Tachyarrhythmias After Congenital Cardiac Operations

BACKGROUND Postoperative tachyarrhythmias remain a common complication after congenital cardiac operations. Dexmedetomidine (DEX), an α-2 adrenoreceptor agonist, can have a therapeutic role in supraventricular tachyarrhythmias for cardioversion to sinus rhythm or heart rate control. Whether routine perioperative use of DEX decreases the incidence of supraventricular and ventricular tachyarrhythmias was studied. METHODS In this prospective cohort study, 32 pediatric patients undergoing cardiothoracic operations received DEX and were compared with 20 control patients who did not receive DEX. RESULTS Dexmedetomidine was started after anesthesia induction and continued intraoperatively and postoperatively for 38±4 hours (mean dose, 0.76±0.04 μg/kg/h). Ten control patients and 2 DEX patients sustained 16 episodes of tachyarrhythmias (p=0.001), including a 25% vs 0% (p=0.01) incidence of ventricular tachycardia and 25% vs 6% (p=0.05) of supraventricular arrhythmias in the control and DEX group, respectively. Transient complete heart block occurred in 2 control patients and in 1 DEX patient. Control patients had a higher heart rate (141±5 vs 127±3 beats/min, p=0.03), more sinus tachycardia episodes (40% vs 6%; p=0.008), required more antihypertensive drugs with nitroprusside (20±7 vs 4±1 μg/kg; p=0.004) and nicardipine (13±5 vs 2±1 μg/kg; p=0.02), and required more fentanyl (39±8 vs 19±3 μg/kg; p=0.005). CONCLUSIONS Perioperative use of dexmedetomidine is associated with a significantly decreased incidence of ventricular and supraventricular tachyarrhythmias, without significant adverse effects.

A mechanism for rapacuronium-induced bronchospasm: M2 muscarinic receptor antagonism.

Background A safe and effective ultra-short-acting nondepolarizing neuromuscular blocking agent is required to block nicotinic receptors to facilitate intubation. Rapacuronium, which sought to fulfill these criteria, was withdrawn from clinical use due to a high incidence of bronchospasm resulting in death. Understanding the mechanism by which rapacuronium induces fatal bronchospasm is imperative so that newly synthesized neuromuscular blocking agents that share this mechanism will not be introduced clinically. Selective inhibition of M2 muscarinic receptors by muscle relaxants during periods of parasympathetic nerve stimulation (e.g., intubation) can result in the massive release of acetylcholine to act on unopposed M3 muscarinic receptors in airway smooth muscle, thereby facilitating bronchoconstriction. Methods Competitive radioligand binding determined the binding affinities of rapacuronium, vecuronium, cisatracurium, methoctramine (selective M2 antagonist), and 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP; selective M3 antagonist) for M2 and M3 muscarinic receptors. Results Rapacuronium competitively displaced 3H-QNB from the M2 muscarinic receptors but not from the M3 muscarinic receptors within clinically relevant concentrations. Fifty percent inhibitory concentrations (mean ± SE) for rapacuronium were as follows: M2 muscarinic receptor, 5.10 ± 1.5 &mgr;m (n = 6); M3 muscarinic receptor, 77.9 ± 11 &mgr;m (n = 8). Cisatracurium and vecuronium competitively displaced 3H-QNB from both M2 and M3 muscarinic receptors but had affinities at greater than clinically achieved concentrations for these relaxants. Conclusions Rapacuronium in clinically significant doses has a higher affinity for M2 muscarinic receptors as compared with M3 muscarinic receptors. A potential mechanism by which rapacuronium may potentiate bronchoconstriction is by blockade of M2 muscarinic receptors on prejunctional parasympathetic nerves, leading to increased release of acetylcholine and thereby resulting in M3 muscarinic receptor–mediated airway smooth muscle constriction.

Rapacuronium Preferentially Antagonizes the Function of M2 versus M3 Muscarinic Receptors in Guinea Pig Airway Smooth Muscle

Background: Rapacuronium, a nondepolarizing muscle relaxant that was proposed as a replacement for succinylcholine for rapid intubation, was withdrawn from clinical use as a result of fatal bronchospasm, but the mechanism of this effect is not known. Preferential antagonism of presynaptic M2 muscarinic receptors versus postsynpatic M3 muscarinic receptors can facilitate bronchoconstriction. The authors questioned whether rapacuronium preferentially antagonized M2 versus M3 muscarinic receptors in intact airway. Methods: Guinea pig tracheal rings were suspended in organ baths and muscle relaxants’ antagonism of prejunctional M2 muscarinic autoreceptors was evaluated by augmentation of muscle contraction elicited by electrical field stimulation. Muscle relaxants’ antagonism of postjunctional M3 muscarinic receptors was assessed by attenuation of muscle contraction elicited by acetylcholine. Results: Rapacuronium displayed a 50-fold higher affinity for antagonism of the M2 versus M3 muscarinic receptor. Moreover, its affinity for the M2 but not the M3 receptor was within concentrations achieved clinically. In addition, rapacuronium caused an increase in baseline tone of airway smooth muscle that was antagonized by atropine but not by previous depletion of nonadrenergic noncholinergic neurotransmitters or by inhibitors of histamine receptors, tachykinin receptors, leukotriene receptors, or calcium channels. Conclusion: These findings are consistent with the hypothesis that rapacuronium may precipitate bronchoconstriction by selective antagonism of the M2 muscarinic receptor on parasympathetic nerves, enhancing acetylcholine release to act upon unopposed M3 muscarinic receptors on airway muscle. An additional mechanism of rapacuronium-induced bronchoconstriction is suggested by increases in baseline muscle tension.

Magnesium supplementation during cardiopulmonary bypass to prevent junctional ectopic tachycardia after pediatric cardiac surgery: A randomized controlled study

OBJECTIVES We analyzed the role of magnesium sulfate (MgSO(4)) supplementation during cardiopulmonary bypass in pediatric patients undergoing cardiac surgery, assessing the incidence of hypomagnesemia and the incidence of junctional ectopic tachycardia. METHODS We performed a randomized, double-blind, controlled trial in 99 children. MgSO(4) or placebo was administered during the rewarming phase of cardiopulmonary bypass: group 1, placebo group (29 patients); group 2, 25 mg/kg of MgSO(4) (30 patients); and group 3, 50 mg/kg of MgSO(4) (40 patients). RESULTS At the time of admission to the cardiac intensive care unit, groups receiving MgSO(4) had significantly greater levels of ionized magnesium (group 1, 0.51 + or - 0.07; group 2, 0.57 + or - 0.09; group 3, 0.59 + or - 0.09). Hypomagnesemia before bypass was common (75%-86.2%) and not significantly different among the groups. The proportion of hypomagnesemia decreased significantly at admission to the cardiac intensive care unit in groups receiving MgSO(4) (group 1, 77.8%; group 2, 63%; group 3, 47.4%). Patients receiving placebo (group 1) had a significantly greater occurrence of junctional ectopic tachycardia than groups receiving MgSO(4) (group 1, n = 5 [17.9%]; group 2, n = 2 [6.7%]; group 3, n = 0 [0%]). Age (<1 month), Aristotle score (>4), and history of cardiac failure were associated with junctional ectopic tachycardia. None of the patients with those characteristics in group 3 had junctional ectopic tachycardia. No association was found between study groups and the Pediatric Risk of Mortality score or length of stay in the cardiac intensive care unit. CONCLUSIONS Supplementation with MgSO(4) during cardiopulmonary bypass seems to reduce the incidence of hypomagnesemia and junctional ectopic tachycardia at admission to the cardiac intensive care unit. This effect seems to be dose related.

The association of renal dysfunction and the use of aprotinin in patients undergoing congenital cardiac surgery requiring cardiopulmonary bypass.

BACKGROUND: The use of large-dose aprotinin during cardiopulmonary bypass (CPB) in adult patients has been linked to postoperative renal dysfunction, but its effect on the pediatric population undergoing complex congenital cardiac operations is not well defined. METHODS: We used a retrospective cohort analysis to evaluate children undergoing cardiac surgery requiring CPB between July 2004 and July 2006. Demographic data and surgical risk quantified by the Aristotle surgical complexity level were analyzed as covariates. Renal dysfunction was defined according to the RIFLE criteria, an international consensus classification which defines three grades of increasing severity of acute kidney injury: risk (Class R), injury (Class I), and failure (Class F) based on serum creatinine values. A univariate and multivariate logistic regression analysis and a propensity score were used to analyze the data. The propensity score was developed using pretreatment covariates associated with the administration of aprotinin. A multivariate logistic regression was then used with the propensity score and intraoperative measures as covariates. A P value <0.05 was considered statistically significant. RESULTS: Among 395 patients who underwent cardiac surgery, 55% received aprotinin and 45% did not. Thirty-one percent of the cohort had previous cardiac surgery; 17% were neonates. According to the RIFLE criteria, 80 of the patients (20.3%) had acute kidney injury in the postoperative period; 53 (13.4%) had risk of renal dysfunction with 23 (5.8%) having injury and four patients (0.7%) having failure. Those receiving aprotinin had a higher incidence of previous cardiac surgery (54.1% vs 5%), sepsis (6.9% vs.0.0%), heart failure (24.8% vs 12.4%), mechanical ventilation (25.2% vs 2.8%), or mechanical circulatory support (6.0% vs.0.6%). More patients had an Aristotle level of 4 (26.6% vs 2.8%) and were treated with diuretics (63.8% vs 26.6%), angiotensin converting enzyme inhibitors (21.1% vs 7.9%), milrinone (25.7% vs 4.5%), and inotropic support (16.1% vs 2.3%). Although there was a significant difference in the unadjusted risk of renal dysfunction, adjustment with the preoperative propensity score revealed that there was no association between aprotinin and renal dysfunction (OR 1.32; 95% CI 0.55–3.19). The duration of CPB was the only independent variable associated with the development of renal dysfunction (OR 1.0; 95% CI 1.009–1.014). CONCLUSIONS: Patients who receive aprotinin are more likely to present with preoperative risk factors for the development of postoperative renal dysfunction. However, when associated risk factors are properly considered, the use of aprotinin does not seem to be associated with a higher risk of developing renal dysfunction in the immediate postoperative period in children.

Acute Hemodynamic Changes After Rapid Intravenous Bolus Dosing of Dexmedetomidine in Pediatric Heart Transplant Patients Undergoing Routine Cardiac Catheterization

BACKGROUND: Dexmedetomidine is a highly selective &agr;2-adrenoceptor agonist with sedative, anxiolytic, and analgesic properties that has minimal effects on respiratory drive. Its sedative and hypotensive effects are mediated via central &agr;2A and imidazoline type 1 receptors while activation of peripheral &agr;2B-adrenoceptors result in an increase in arterial blood pressure and systemic vascular resistance. In this randomized, prospective, clinical study, we attempted to quantify the short-term hemodynamic effects resulting from a rapid IV bolus administration of dexmedetomidine in pediatric cardiac transplant patients. METHODS: Twelve patients, aged 10 years or younger, weighing ⩽40 kg, presenting for routine surveillance of right and left heart cardiac catheterization after cardiac transplantation were enrolled. After an inhaled or IV induction, the tracheas were intubated and anesthesia was maintained with 1 minimum alveolar concentration of isoflurane in room air, fentanyl (1 &mgr;g/kg), and rocuronium (1 mg/kg). At the completion of the planned cardiac catheterization, 100% oxygen was administered. After recording a set of baseline values that included heart rate (HR), systolic blood pressure, diastolic blood pressure, central venous pressure, systolic pulmonary artery pressure, diastolic pulmonary artery pressure, pulmonary artery wedge pressure, and thermodilution-based cardiac output, a rapid IV dexmedetomidine bolus of either 0.25 or 0.5 &mgr;g/kg was administered over 5 seconds. The hemodynamic measurements were repeated at 1 minute and 5 minutes. RESULTS: There were 6 patients in each group. Investigation suggested that systolic blood pressure, diastolic blood pressure, systolic pulmonary artery pressure, diastolic pulmonary artery pressure, pulmonary artery wedge pressure, and systemic vascular resistance all increased at 1 minute after rapid IV bolus for both doses and decreased significantly to near baseline for both doses by 5 minutes. The transient increase in pressures was more pronounced in the systemic system than in the pulmonary system. In the systemic system, there was a larger percent increase in the diastolic pressures than the systolic pressures. Cardiac output, central venous pressure, and pulmonary vascular resistance did not change significantly. HR decreased at 1 minute for both doses and was, within the 0.5 &mgr;g/kg group, the only hemodynamic variable still changed from baseline at the 5-minute time point. CONCLUSION: Rapid IV bolus administration of dexmedetomidine in this small sample of children having undergone heart transplants was clinically well tolerated, although it resulted in a transient but significant increase in systemic and pulmonary pressure and a decrease in HR. In the systemic system, there is a larger percent increase in the diastolic pressures than the systolic pressures and, furthermore, these transient increases in pressures were more pronounced in the systemic system than in the pulmonary system.

Effect of dexmedetomidine on pulmonary artery pressure after congenital cardiac surgery: A pilot study.

Objective: To characterize the effects of dexmedetomidine on the pulmonary artery pressure in patients after congenital cardiac surgery. Design: Prospective observational pilot study. Setting: Pediatric cardiac intensive care unit at a university hospital. Patients: Twenty-two patients who received dexmedetomidine after cardiothoracic surgery. Interventions: None. Measurements and Main Results: An echocardiogram was performed at three time points: 1) baseline (T0); 2) 6 mins after dexmedetomidine loading (T1); and 3) 1 hr after initiation of dexmedetomidine infusion (T2). Transthoracic echocardiography was used to estimate pulmonary artery pressure based on tricuspid regurgitant velocity (4 × Velocity2) plus central venous pressure. Twenty-two patients aged 0.9 yrs old (interquartile range, 7.9) were enrolled at a median of 1 hr (1.5) after surgery. Dexmedetomidine loading, 0.62 &mgr;g/kg (0.5), was given in all patients followed by 0.5 &mgr;g/kg/hr (0.6) at T1 and 0.65 &mgr;g/kg/hr (0.5) at T2. None of the patients had any increase in pulmonary artery pressure. Overall, the pulmonary artery pressure decreased from 30 mm Hg (13) at T0 to 24 mm Hg (10) at T1 and 26 mm Hg (8) at T2 (p < .001). The pulmonary artery pressure/systemic systolic blood pressure ratio decreased from 33% (12) at T0 to 23% (15) at T1 and 25% (13) at T2 (p = .002). There was no difference in the left ventricular function, Fio2, oxygen %, Po2, CO2, and vasoactive agents. Conclusions: Administration of dexmedetomidine after congenital cardiac surgery was not associated with any increase in pulmonary artery pressure.

Neuromuscular Blocking Agents' Differential Bronchoconstrictive Potential in Guinea Pig Airways

Background:Neuromuscular blocking agents are designed to antagonize nicotinic cholinergic receptors on skeletal muscle but also antagonize muscarinic receptors. Several muscle relaxants have the potential to promote bronchoconstriction due to unintended effects exemplified by histamine release of atracurium or mivacurium and detrimental interactions with muscarinic receptors by rapacuronium. Although interactions of muscle relaxants with muscarinic receptors have been extensively characterized in vitro, limited information is available on their potential interactions with airway tone in vivo. Methods:Changes in pulmonary inflation pressures and heart rates induced by vagal nerve stimulation and intravenous acetylcholine were measured in the absence and presence of increasing doses of gallamine, pancuronium, mivacurium, vecuronium, cisatracurium, rocuronium, or rapacuronium in guinea pigs. Mivacuriums and rapacuroniums potential of inducing bronchoconstriction by histamine release was also evaluated. Results:Rapacuronium potentiated both vagal nerve–stimulated and intravenous acetylcholine–induced increases in airway pressures, which were totally blocked by atropine but not pyrilamine. Vecuronium, rocuronium, mivacurium, and cisatracurium were devoid of significant airway effects. Mivacurium, at high doses, increased pulmonary inflation pressures, which were attenuated by pyrilamine. Conclusion:Rapacuronium was unique among muscle relaxants evaluated in that it potentiated both vagal nerve– and intravenous acetylcholine–induced bronchoconstriction with no evidence of histamine release. The dual detrimental interactions of rapacuronium with muscarinic receptors previously demonstrated in vitro correlate with in vivo muscarinic receptor mechanisms of bronchoconstriction and may account for the profound bronchoconstriction seen with its clinical use. These findings may establish pharmacologic characteristics to avoid with new muscle relaxants intended for clinical use.

Dexmedetomidine: therapeutic use for the termination of reentrant supraventricular tachycardia.

OBJECTIVES The current drug of choice for reentrant supraventricular tachycardia (SVT) is adenosine followed by verapamil or diltiazem. Although limitations and significant adverse events have been encountered over the years, an alternative effective and safe agent has not been available. Dexmedetomidine has recently been shown to have potential antiarrhythmic effects, and here we describe our experience in the acute termination of reentrant SVT. DESIGN Retrospective case series. SETTING Quaternary University Childrens Hospital, Cardiac Intensive Care Unit. PATIENTS Patients who received dexmedetomidine for SVT in the past 5 years. INTERVENTIONS None. OUTCOME MEASURES SVT episodes terminated with dexmedetomidine were compared with episodes terminated with adenosine. RESULTS Fifteen patients, median age of 10 days (6-16), were given 27 doses of dexmedetomidine, mean dose 0.7 ± 0.3 mcg/kg, for a total of 27 episodes of SVT. Successful termination occurred in 26 episodes (96%) at a median time of 30 seconds (20-35). Duration of sinus pause was 0.6 ± 0.2 seconds, there was one episode of hypotension and no bradycardia and sedation lasted for 34 ± 8 minutes. Five patients received 27 doses of adenosine, with an overall successful cardioversion in 17 patients (63%) (P= .0017). Transient bradycardia and hypotension was seen in three patients (11%), agitation in 16 patients (59%), and broncospasm in one patient. Median sinus pause was 2.5 seconds (2-9) (P < .001). CONCLUSIONS Dexmedetomidine appears to have novel antiarrhythmic properties for the acute termination of reentrant SVT. Although adenosine is very effective, dexmedetomidine may prove to possess a more favorable therapeutic profile with increased effectiveness and fewer side effects.