Pulmonary hypertension is defined as a mean pulmonary arterial pressure of 25 mm Hg at rest (30 mm Hg during exercise) in association with variable degrees of pulmonary vascular remodeling, vasoconstriction, and in situ thrombosis (1,2). The multiple etiologies of pulmonary hypertension were reclassified at a World Health Organization symposium (2) and are applicable to both adults and children.
Children with pulmonary hypertension typically have an increased requirement for medical resources (3). Many receive general anesthesia for the multiple diagnostic and therapeutic procedures that are required for the assessment and management of their pulmonary hypertension and the underlying disease that caused it. Additionally, these patients may undergo general anesthesia for indications unrelated to pulmonary hypertension. It is widely accepted that pulmonary hypertensive patients deserve special consideration because they are at increased risk from anesthesia and surgery (4–8).
Ketamine has been used successfully in the anesthetic management of patients with severe pulmonary hypertension (9–14). Nevertheless, the use of ketamine remains controversial because it increases pulmonary arterial pressure in adult patients (15,16). A small number of studies evaluating the effect of ketamine on pulmonary artery pressure in children have been conducted with conflicting results (17–20). Our clinical experience has been that ketamine is a useful anesthetic for children with pulmonary hypertension. Accordingly, we performed this prospective, open label study to evaluate the hemodynamic responses to ketamine in children with pulmonary hypertension.
The study was approved by the IRB and written informed parental consent was obtained for all study subjects. Patients ranging in age from 3 mo to 18 yr with suspected or proven pulmonary hypertension were screened for study enrollment. All of these children had been evaluated in our institution’s Vera Moulton Wall Center for Pulmonary Vascular Disease and scheduled for cardiac catheterization with general anesthesia. Indications for cardiac catheterization included assessment of the patient’s cardiovascular status and response to pulmonary vasodilator therapy. Criteria for exclusion from the study included history of allergy to ketamine, neurologic events such as stroke, cerebral hemorrhage and increased intracranial pressure, or planned assisted or controlled ventilation of the lungs during anesthesia for the catheterization procedure. Subjects were excluded during the study if the mean pulmonary artery pressure at catheterization was measured to be <25 mm Hg.
Anesthesia care was provided by a pediatric cardiac anesthesiologist. Premedication with midazolam by either the IV or oral route was administered if the anesthesiologist deemed it appropriate. Standard monitoring was applied, including electrocardiogram, pulse oximetry, temperature, noninvasive arterial blood pressure, and end-tidal CO2, and inspired and exhaled sevoflurane concentrations. If not present preoperatively, a peripheral IV catheter was inserted after the patient was anesthetized. Anesthesia was induced with sevoflurane in air and then maintained with sevoflurane (1.0 minimum alveolar anesthetic concentration [MAC], age-adjusted) and air via a tight-fitting facemask and circle breathing system. If patients were receiving supplemental oxygen preoperatively, oxygen was continued at a comparable inspired oxygen concentration during induction and maintenance. No changes were made to the inspired oxygen concentration during the study period. Femoral arterial and venous access for cardiac catheterization was established after general anesthesia had been induced and the insertion sites numbed with lidocaine.
Once baseline catheterization measurements were obtained, IV ketamine (2 mg/kg) was administered over 5 min. The inspired sevoflurane concentration was reduced to 0.5 MAC and the inspired oxygen concentration kept unchanged. Immediately after completion of the initial ketamine dose, a continuous IV ketamine infusion at 10 μg · kg−1 · min−1 was started. If the level of anesthesia was considered inadequate, the ketamine infusion rate was increased as necessary in increments of 10 μg · kg−1 · min−1. Anesthesia was maintained with this combination of ketamine and sevoflurane until the end of data collection. Midazolam (0.05–0.1 mg/kg IV) was administered at the end of the procedure to diminish the risk of ketamine-associated emergence delirium. Patients recovered in a pediatric postoperative care unit until ready to be discharged home or to a hospital ward and were monitored for adverse events, including hemodynamic instability, respiratory depression, and hallucinations.
Cardiac catheterization was performed by one of two pediatric interventional cardiologists participating in the study (J.F., S.P.). Data were obtained at four time points: immediately before ketamine administration (T1, baseline), 5 min (T2), 10 min (T3), and 15 min (T4) after completion of the initial (2 mg/kg) load of ketamine. Hemodynamic measurements including systolic, diastolic and mean aortic and pulmonary artery pressures, pulmonary capillary wedge pressures (estimating left atrial pressures), mixed venous and arterial oxygen saturations (by co-oximetry), and blood gas analyses were obtained for each time point. Cardiac index was determined by thermodilution or Fick methods with assumed values for oxygen consumption (LA Farge nomograms) as appropriate. Pulmonary and systemic vascular resistance indexes were calculated using standard formulae.
The study sample size was estimated based on unpublished pilot data from five patients who received intraoperative ketamine. We planned the study to resolve a 20% change in our primary outcome measure (pulmonary vascular resistance) from baseline 10 min after ketamine administration. A sample size estimate based on a one-sample t-test of pulmonary vascular resistance change scores (assuming 80% power with type I error rate [α] of 0.05) yielded a sample size of 15 patients.
Demographic, anesthetic, and cardiac catheterization data were recorded. Perioperative adverse events were noted. Descriptive statistics were used to summarize demographic and outcome data and are presented as median (interquartile range) when not distributed normally. Normal distribution of data was determined using QQ plots and the Kolmogorov–Smirnov test. Where data were not normally distributed, variables were log-transformed and normality was confirmed before application of parametric tests. Longitudinal data analysis was performed using repeated measures ANOVA taking time as a repeated measure. Sphericity of the common covariance matrix of the transformed within-subject variables was tested using Mauchly’s sphericity test. Unadjusted univariate P values are presented when sphericity is valid, and multivariate Wilks’ Lambda P values are presented when the sphericity assumption is violated. Post hoc power analysis was computed based on two-sample t-test of log-transformed data. Analyses were performed with Microsoft Excel and SAS 9.1 statistical package (Cary, NC) with P < 0.05 considered statistically significant.
Eighteen children were enrolled in the study. Three patients were excluded from analyses because their mean pulmonary artery pressures at time period T1 were <25 mm Hg. Fifteen patients completed study protocol. Their demographic data are presented in Table 1. Nine (60%) of the 15 children had a history of congenital heart disease (CHD) related to congenital systemic-to-pulmonary shunts, 5 (33%) were diagnosed with idiopathic pulmonary arterial hypertension, and 1 (7%) had a history of a diaphragmatic hernia. Cardiac defects included ventricular septal defect (n = 2, unrepaired) atrial plus ventricular septal defects (n = 4, one repaired surgically) and patent ductus arteriosus (n = 3, all repaired).
At the time of catheterization, 80% of subjects were receiving medical therapy for pulmonary hypertension. The number (%) of patients receiving these medications were sildenafil: 9 (60%), bosentan: 8 (53%), epoprostenol or treprostinil: 7 (47%), oxygen: 5 (33%), and nitric oxide: 1 (7%). Eleven (73%) patients were receiving a combination of pulmonary hypertensive medications. In addition, 10 (67%) subjects were receiving anticoagulants (aspirin or coumadin) and 9 (60%) were taking heart failure medications (digoxin, diuretics). All patients were rated ASA physical status III or IV.
Sevoflurane concentrations (mean ± sd) at the four time measurements were T1: 1.9% ± 0.5%; T2: 1.1% ± 0.3%; T3: 1.1% ± 0.3%; T4: 1.1% ± 0.3%. All patients received the same ketamine infusion rate (10 μg · kg−1 · min−1). Seven subjects received supplemental oxygen (median Fio2 = 0.3) because they were chronically receiving oxygen therapy or had desaturated during initiation of sevoflurane induction.
Hemodynamic and blood gas values for each time point are presented in Table 2. At baseline, median pulmonary vascular resistance of study subjects was 11.3 Wood units, and the median ratio of mean pulmonary artery pressure to mean systemic arterial pressure was 0.85. One-third of the patients had suprasystemic pulmonary pressures at baseline. Median baseline cardiac index for study patients (4.18 L · min−1 · m−2 for children without intracardiac shunt) was within the normal range and did not change significantly after ketamine administration.
Pulmonary vascular resistance index values at the four time points for each patient are shown in Figure 1. Calculated pulmonary vascular resistance (the primary outcome variable) after ketamine administration at T2, T3, and T4 was similar to the baseline value before ketamine at T1 (P = 0.92). Computed post hoc power estimates for log-transformed pulmonary vascular resistance measurements indicated that the study was adequately powered (81.5%) to detect a 20% change from baseline values. There was no statistically significant relationship between baseline pulmonary vascular resistance and the change from baseline values of pulmonary vascular resistance at time point T4. Baseline pulmonary vascular resistance and change of pulmonary vascular resistance over time (T4 compared with T1) were unrelated to Fio2. The median heart rate slowed from 99 to 94 bpm after ketamine administration (P = 0.016) and median Pao2 increased from 95 mm Hg at T1 to 104 mm Hg at T4 (P = 0.007). Other hemodynamic variables remained similar to baseline (T1) values.
Subjects with CHD were compared with those with no history of CHD. There was no difference between these two groups in demographic, hemodynamic, and arterial blood-gas outcome variables. There was no significant change in pulmonary vascular resistance over time between patients with CHD and those who did not have CHD (P = 0.2, ANOVA). Post hoc analysis showed 88% power to resolve a clinically significant 20% difference between groups in pulmonary vascular resistance at T3 (α = 0.05).
No adverse events attributable to ketamine were noted during the intra- and postoperative periods. The incidence of emesis during patients’ stay in the postoperative recovery unit was 20%. Emergence delirium was not observed.
Chart review showed 10 subjects were evaluated by catheterization for change in pulmonary vascular resistance during trial exposure to vasodilator therapy; pulmonary vascular resistance decreased in eight patients and remained unchanged in two with repaired patent ductus arteriosus defects. Of the five patients not tested, one subsequently underwent successful repair of atrial and ventricular septal defects and the other four were receiving vasodilator therapy.
Our study differs from previous investigations of ketamine’s effects on pulmonary vascular resistance in children in that subjects had severe pulmonary hypertension and baseline anesthesia was sevoflurane rather than IV or oral drugs. There were two main findings. First, ketamine did not increase pulmonary vascular resistance when administered to children with preexisting pulmonary hypertension who were breathing spontaneously and receiving sevoflurane 0.5 MAC. Second, in contrast to previous studies (17–19), alterations in pulmonary vascular resistance after the administration of ketamine were unrelated to the severity of pulmonary hypertension at baseline.
Twelve (80%) of our study patients had a baseline pulmonary vascular resistance index more than 6 Wood units. For comparison, approximately 7%–14% of subjects in previous investigations (17–21) met this criterion. Given the degree of pulmonary artery pressure increase, our study patients would be regarded as a high-risk group for anesthesia. One-third had baseline suprasystemic pulmonary arterial hypertension, which is predictive of major complications associated with noncardiac surgery or cardiac catheterization (4,5). The majority of subjects had some reactivity to pulmonary vasodilator therapy; only two patients appeared to have fixed pulmonary vascular resistance. The perioperative management of pulmonary hypertension is a challenge for the anesthesiologist, because the risk of life-threatening events is markedly increased when compared with most other pediatric patient populations (4). Several mechanisms have been implicated, including pulmonary hypertensive crises, inadequate preload to the right ventricle, increased afterload of the right ventricle, myocardial dysfunction, hypotension, ischemia, and arrhythmia (4–7).
Ketamine anesthesia offers several benefits for pediatric patients with pulmonary hypertension who are undergoing cardiac catheterization. Ketamine maintained systemic arterial pressure and systemic vascular resistance (trended towards an increase in mean arterial pressure, P = 0.06) (21). This might be helpful in preserving coronary blood flow to the hypertensive right ventricle. In contrast, volatile anesthetics and IV drugs such as propofol decrease systemic arterial pressure (21–23). The observed slight decrease in heart rate after ketamine administration might have prolonged the period during the cardiac cycle during which the right ventricle received coronary flow. Additionally, maintenance of systemic vascular resistance and left ventricular systolic pressure might have limited the undesirable ventricular septal shift that occurs when the septum is intact and right ventricular pressures are high. Leftward shift of the ventricular septum decreases left ventricular volume and limits left ventricular stroke volume, thereby decreasing systemic cardiac output and coronary flow (7). In patients with pulmonary hypertensive and intracardiac shunt (for example, Eisenmenger’s syndrome), ketamine maintains the ratio of pulmonary and systemic blood flow better than anesthetics, such as propofol, that decrease systemic vascular resistance and enhance right-to-left shunt (21,23). Ketamine may also enhance cardiac performance by central sympathetic stimulation and inhibition of neuronal catecholamine uptake (24). These advantages of ketamine might be negated if ketamine increased pulmonary arterial pressure and pulmonary vascular resistance. However, pulmonary vascular resistance was unchanged in our study during sevoflurane anesthesia.
Additionally, ketamine did not enhance the respiratory depressant effects of sevoflurane. Indeed, arterial pH and Paco2 were unaltered after ketamine administration and Pao2 improved. Maintaining normoxia was probably beneficial because hypercarbia and hypoxia can both augment pulmonary hypertension. Increases in pulmonary vascular resistance in response to acidosis are small in the presence of normal alveolar oxygen tensions, but much larger in the presence of alveolar hypoxia (7). The relative preservation of respiratory effort allowed us to manage the patients without instrumenting the airway and controlling ventilation (25). Although Carmosino et al. (4) found no association between airway management and complications, we prefer maintenance of the natural airway when possible because both intubation and extubation of the trachea have been associated with life-threatening or fatal escalation of pulmonary artery pressures (26). In addition, our aim was to implement an anesthetic plan that would minimize physiologic circulatory changes compared to the awake state, including the application of positive pressure ventilation. By using this approach, we hoped to enhance the clinical applicability of catheterization data obtained.
Patients with pulmonary arterial hypertension related to congenital systemic to pulmonary shunts have a slower progressive course than do idiopathic pulmonary arterial hypertension patients (27) and it may be that the various clinical classes of pulmonary hypertension have differing responses to drugs. Thus, the finding that the hemodynamic responses to ketamine for study subjects with CHD were no different from those noted in patients without CHD is interesting and warrants further study.
Animal investigations suggest that the effects of ketamine on pulmonary vasculature are complex. Ketamine increased concentrations of epinephrine and norepinephrine in plasma (28) and increased pulmonary vascular resistance in isolated rat lungs (29). However, later work with several animal models found that ketamine caused direct pulmonary artery vasodilation. The effect is endothelium-independent and mediated by a reduction of calcium in vascular smooth muscle cells by inhibitions of both voltage-gated calcium influx and norepinephrine-induced calcium release from intracellular stores (30–34). Ketamine has also been noted to attenuate endothelium-dependent pulmonary vasorelaxation in response to acetylcholine and bradykinin by inhibiting both the nitric oxide and the endothelium-derived hyperpolarizing factor components of the response (35,36). In summary, animal data show ketamine has the potential to increase or inhibit pulmonary vasodilation and the clinical effect most likely depends on the integration of multiple mechanisms (7).
Results of investigations of the effects of ketamine on pulmonary vasomotor tone in humans are also conflicting. One-lung ventilation with ketamine resulted in a more stable Pao2 and pulmonary shunt when compared with volatile anesthetics (37). Ketamine was initially reported to cause an increase in pulmonary vascular resistance in adults during spontaneous respiration (15,16). A study in children conducted at high altitude reported similar results but blood gas data were not provided (17). The extent of increase of pulmonary vascular resistance after ketamine was found to be related linearly to the baseline level of pulmonary vascular resistance. In contrast, three studies in children with CHD found that ketamine did not cause significant pulmonary vascular reactivity (19–21). However, these study designs differ from the present study. Hickey et al. measured hemodynamic responses to ketamine during spontaneous ventilation in tracheally intubated infants who were receiving minimal ventilatory support with an intermittent mandatory ventilation of 4 and Fio2 of 0.3–0.4. No significant changes were found in pulmonary vascular resistance index in patients with normal pulmonary vascular resistance nor in those with preexisting increased pulmonary vascular resistance (20). Wolfe et al. measured the hemodynamic responses of children with repaired CHD to hypoxia, hyperoxia, and ketamine when sedated and breathing spontaneously (18). A subgroup with increased pulmonary vascular resistance at baseline (room air) had markedly increased pulmonary vascular resistance when exposed to 16% oxygen and then to ketamine. This study was conducted at 1200 m above sea level and specifically selected patients with increased pulmonary vascular resistance who also were chronically exposed to hypoventilation, airway obstruction and hypoxia. Baseline Pao2 without supplemental oxygen was between 56 and 66 mm Hg. These two reports (18,20) are complementary in that they illustrate the importance of maintaining normoxia in patients with pulmonary hypertension. Our study also showed that ketamine was well tolerated in the presence of normoxia and did not increase pulmonary vascular resistance in the presence of sevoflurane. Additionally, changes in pulmonary vascular resistance after ketamine administration were independent of baseline pulmonary vascular resistance values, suggesting that ketamine or sevoflurane anesthesia may be a suitable technique for patients with severe pulmonary hypertension.
Adverse effects of ketamine appeared to be minimal in this study. Specifically, ketamine was not associated with a clinically significant increase in salivation, hallucinations, or a decrease in cardiac index (24). We did not give our patients antisialogogue, as heart rate increases can potentially affect hemodynamic information.
Study limitations include constraints of clinical considerations on protocol design. Children enrolled in this study were undergoing cardiac catheterization under general anesthesia to assess the severity of their pulmonary hypertension, further define cardiac anatomy and function, and to determine their responses to pulmonary hypertension therapies. It is our usual practice in young children to defer placement of an IV catheter until after inhaled induction of anesthesia, and we have found that pulmonary hypertensive patients can be transitioned successfully to IV ketamine anesthesia after induction with sevoflurane. However, in designing this study protocol, we decided that it was scientifically appropriate to continue administration of sevoflurane after initiation of ketamine to limit uncontrolled study variables. If sevoflurane had been discontinued when ketamine was administered, data interpretation would become confounded because any alteration from baseline of outcome variables could be either from the introduction of ketamine or the withdrawal of sevoflurane. Results should be viewed in the context of the background anesthetic, because sevoflurane is probably a pulmonary vasodilator. Cardiac output was not measured in 10 of the 15 patients (intracardiac shunt present in 5) but rather calculated from an assumed oxygen consumption. This is a potential source of error. Study findings may not be applicable to all pulmonary hypertensive children because the investigation was conducted at low altitude and there was a preponderance of subjects with severe pulmonary hypertension.
We conclude that ketamine (load and subsequent infusion) did not exacerbate pulmonary hypertension in spontaneously breathing children anesthetized with sevoflurane in air and suggest that the combination of these anesthetics may be a useful anesthetic technique for cardiac catheterization in children with pulmonary hypertension.
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