The combination of local anesthetic and sedative drugs is now administered routinely to patients undergoing flexible bronchoscopy to facilitate examination of the tracheobronchial tree, carry out the necessary diagnostic or interventional procedures and provide patient comfort (1–3). Local anesthesia of the airways is achieved with topical lignocaine. Benzodiazepines and opioids are routinely used for the purpose of sedation during bronchoscopy (4). The untoward effects of benzodiazepines and opioids include respiratory and myocardial depression, hypotension and bronchospasm (5). When used together these drugs may act synergistically warranting caution and careful monitoring during the procedure (5). Lung transplant recipients undergo several bronchoscopy procedures and therefore need to be well sedated (2). In our clinical experience, we noted that patients with cystic fibrosis (CF) tended to need higher doses of sedatives during bronchoscopy. To our knowledge there are no data in the literature which describe the sedative drug requirements during flexible bronchoscopy in lung transplant recipients. We undertook this study to assess the sedative drug doses administered during flexible bronchoscopy in lung transplant recipients and to assess if there is a change in the dosage requirements over time following lung transplantation.
MATERIALS AND METHODS
We analyzed 773 transbronchial biopsy (TBB) procedures performed via flexible bronchoscopy in 140 consecutive lung transplant recipients (male:female, 71:69). We included only TBB procedures to maintain a uniform cohort of procedures for purposes of comparison. A TBB procedure was excluded if combined with any other procedure such as pleurodesis or gastrointestinal endoscopy, patient receiving ventilator support or if the patient died within the first 3 months following lung transplantation. Reasons for transplantation included emphysema 46 (33%), CF 42 (30%), idiopathic pulmonary fibrosis (IPF) 25 (18%), pulmonary hypertension 8 (6%), bronchiectasis 5 (4%), pulmonary lymphangiomyomatosis 5 (4%), congenital heart disease 4 (3%), eosinophilic granuloma 3 (2%), silicosis 1 (1%) and asthma 1 (1%). All patients received triple-drug immunosuppression (cyclosporine/tacrolimus, azathioprine/mycophenolate mofetil, and prednisolone) posttransplantation (6).
Surveillance, diagnostic, and follow-up transbronchial biopsy procedures were performed as per protocol following lung transplantation or for indications as described earlier (7–10). Flexible bronchoscopy was performed under local anesthesia and sedation. All patients received supplemental nasal oxygen. Acute hypoxemia during flexible bronchoscopy was managed using the St Vincent's stepwise approach (11, 12). Sedation was achieved with intermittent boluses of intravenous midazolam and fentanyl (3). Optimal sedation was considered to have been achieved when FB was comfortably facilitated. The following end points were used as a guide to adequate sedation: eye closure, lack of movement and swallowing with movement of the bronchoscope, unclenching of the fists and the absence of grimacing or other facial responses. Intravenous propofol boluses of 10 to 30 mg were administered when optimal sedation was not achieved with midazolam dosage of 0.20 to 0.25 mg/kg and fentanyl dosage of 2 to 2.5 micrograms/kg. These limits were exceeded occasionally when patients needed boluses late in their procedure. Once propofol was used due to inability to achieve optimal sedation with midazolam and fentanyl, it was used for all subsequent bronchoscopy procedures in that patient. Propofol was also used in one patient with emphysema who was allergic to midazolam.
To compare two independent groups The Mann Whitney U test was used. Disease groups were categorized as emphysema, CF, IPF and the “other diagnoses.” To test the effect of time (days) for midazolam (mg/kg) and fentanyl (micrograms/kg), a linear mixed effect model with dependent variable “dose,” “disease groups” as a fixed factor, “subject” as a random factor and “time after transplantation” as independent variable was applied. The variable “dose” was logarithmically transformed to stabilize the unequal variances across groups and days. All calculations were done by a statistician using the statistical software S-plus v6.1.
The mean age of the 140 lung transplant recipients at the time of transplantation was 40±13 years. The mean age for patients with CF was significantly lower compared to all the other groups (P<0.0001) (Table 1). The mean age for patients with emphysema was also significantly higher compared to those amongst the ‘other diagnoses' group. The mean number of TBB procedures performed per patient were 5.5±3.6. There was no significant difference in the mean number of TBB procedures performed in the four groups of patients with CF, IPF, emphysema or the other diagnoses group (P>0.05). The mean midazolam and fentanyl doses and the body mass indices at the time of the TBB procedure in the various disease groups are presented in Table 1. Overall, the mean dose of midazolam and fentanyl administered were 0.15±0.07 mg/kg (range 0.02 to 0.44 mg/kg) and 1.8±0.8 micrograms/kg (range 0.1 to 6.67 micrograms/kg) respectively. The midazolam and fentanyl doses administered to patients with CF were the highest compared to those with other disease types (P<0.0001). The mean body mass index was 21.8±3.5 (range 14.5 to 35.2). The body mass index in patients with cystic fibrosis was significantly lower compared to the other groups (P<0.0001) (Table 1).
The mean midazolam doses administered to bilateral, heart-lung and single lung transplant recipients were 0.17±0.07 mg/kg, 0.15±0.05 mg/kg and 0.11±0.04 mg/kg respectively. The mean fentanyl doses administered to bilateral, heart-lung and single lung transplant recipients were 2.0±0.9 micrograms/kg, 1.6±0.5 micrograms/kg and 1.42±0.5 micrograms/kg respectively. The midazolam dose administered to bilateral lung transplant recipients was significantly higher compared to single lung transplant recipients (P<0.0001) and there was a trend for them to be higher compared to the heart-lung transplant recipients (P=0.08). The fentanyl doses administered were significantly higher in bilateral lung transplant recipients compared to heart-lung and single lung transplant recipients (P<0.0001). Both the midazolam (P<0.0001) and fentanyl (P<0.01) doses administered to heart-lung transplant were significantly higher compared to single lung transplant recipients.
Examining the doses of midazolam and fentanyl administered over time following transplantation, there was a significant linear (P<0.001) and quadratic (P=0.0023) effect of time for midazolam and a significant linear (0.003) and a trend (P=0.08) for a quadratic effect for fentanyl (Fig. 1, Figure 2). This means that considering the first doses administered as baseline there is a significant increase in both the midazolam and fentanyl doses over time following lung transplantation. This increase reaches a maximum and there seems to be a trend to decrease later, but does not reach the baseline doses with midazolam and fentanyl. Significant risk factors associated with this increase in the midazolam and fentanyl doses were the diagnosis of CF compared to those with IPF and emphysema and also bilateral lung transplant recipients compared to heart-lung and single lung transplant recipients (Fig. 1 and 2). Age was not included in the model, as younger patients were expected in the CF group (Table 1).
Overall propofol was used during 17 procedures in seven patients, all of whom had CF because of inability to achieve optimal sedation despite high doses of midazolam and fentanyl. Optimal sedation to facilitate bronchoscopy had been achieved in these patients with a combination of midazolam and fentanyl on at least one prior flexible bronchoscopy procedure after transplantation. The mean midazolam and fentanyl dosages used prior to the first use of propofol were 0.24±0.06 mg/kg (range 0.16 to 0.32 mg/kg) and 2.2±1.2 micrograms/kg (range 0.18 to 3.8 micrograms/kg) respectively. Propofol was first administered to these patients at a mean and median postoperative day of 195±301 days and 70 days respectively following lung transplantation. The mean dosage of propofol administered was 212±152 mg (range 30 to 600 mg) or 3.5±2.4 mg/kg (range 0.5 to 9.0 mg/kg). Sedation reversal medication (flumazenil and/or naloxone) were administered on six occasions for persistent hypoxemia (12). Pneumothorax following TBB occurred during 11/773 (1.4%) procedures and was treated with insertion of an intercostal drainage tube. Bleeding during bronchoscopy was managed bronchoscopically as described before and did not lead to an increase in sedative drug administration (13). Two patients developed atrial fibrillation on one occasion each.
There is a large demand for sedation with endoscopy (14). A combination of benzodiazepine and narcotic drugs, such as midazolam (0.075 mg/kg) and fentanyl (50 – 100 μg) are commonly used during flexible bronchoscopy (5). Midazolam has a rapid onset and short duration of action, and reliably provides amnesia (15, 16). Fentanyl is a potent short acting opioid in low doses, which has a greater analgesic potency than morphine with a rapid onset and limited duration of action (5). Incremental intravenous dosages of such drugs in the appropriately monitored patient are safe, reliable and facilitate conduct of the procedure (5). Lung transplant recipients frequently undergo transbronchial biopsy for a diagnostic indication, surveillance or follow up after rejection. There was no significant difference in the TBB procedures performed in the four groups of patients. This is the first report which describes and analyzes in detail the sedative drug requirements during flexible bronchoscopy in lung transplant recipients. The findings of our study show that a large range of sedative doses are required during flexible bronchoscopy in lung transplant recipients. The doses of sedative medication administered are significantly higher in patients with CF. Also, there is a significant increase with time after transplantation in the doses of the sedative medication used. Within the various disease groups, this increase is significantly higher in the CF population. Furthermore, the combination of midazolam and fentanyl was not effective in some patients with cystic fibrosis in whom propofol was effectively used as an alternative.
The mechanism for an increased sedative dose requirement after transplantation is not clear. None of the patients were on long term narcotics. Analgesics or tranquilizers are not routinely administered to lung transplant recipients except in the first few weeks following transplantation for postoperative pain relief. This approach was used uniformly in all patients. Furthermore, the requirement of sedative medication was much higher during the later course after transplantation rather than early posttransplantation. Following lung transplantation patients have a significant increase in their body mass index, which may be attributed to the reduced morbidity from chronic respiratory failure posttransplantation and to the effects of corticosteroids. The body mass index can potentially impact on the volume distribution of the drugs used. The CF patients had a significantly lower body mass index after transplantation compared to the other disease groups but required a significantly higher dose of sedatives. Both midazolam and fentanyl are lipid soluble, have a high first pass metabolism and also have a high volume of distribution. Hence, we hypothesize that the increased requirement of sedative medication following lung transplantation is unlikely to be due to increase in body mass index and volume redistribution and rather favors an increased drug clearance mechanism, which remains to be elucidated. A larger volume of distribution and greater metabolic and renal clearance has been suggested as a mechanism for enhanced drug clearance in patients with CF (17). Following heart and lung transplantation, patients with CF have demonstrated a higher cyclosporine clearance compared to patients with Eisenmenger's syndrome (18). Hence patients with CF receive larger doses of cyclosporine compared to other lung transplant recipients (6). Like cyclosporine, midazolam is also eliminated almost entirely by metabolism and principally by cytochrome P450 3A (19, 20). We hypothesize that similar to cyclosporine, there may be a higher clearance of midazolam in patients with CF. However, this hypothesis would need to be confirmed prior to using higher dosages of midazolam in selected patients with CF instead of an alternative drug such as propofol.
Propofol was effectively used in seven lung transplant recipients in our study in whom adequate sedation could not be achieved with high doses of midazolam and fentanyl. Propofol is a lipid soluble phenol derivative that has an extremely short duration of action and hence is a useful drug for outpatient general anesthesia (5). It is rapidly eliminated by hepatic and extrahepatic metabolism. Although propofol may provide excellent sedation in low doses (21), it is very easy for patients to cross from light sedation to deep sedation or general anesthesia (22). Although there are reports with the use of nurse administered propofol during gastrointestinal endoscopy (23), in this study it was administered only by an anesthetist.
To summarize, the findings of this observational study show that lung transplant recipients with CF need higher doses of sedative medication during flexible bronchoscopy. There is an increase in sedative drug requirement with time for both midazolam and fentanyl after transplantation, which is significantly higher in patients with CF. This information is important for the bronchoscopist as well as the anesthetic and nursing staff for optimal use of sedative drugs. Propofol is a useful alternative in those patients with CF in whom adequate sedation to facilitate flexible bronchoscopy is not achieved with usual dosages of midazolam and fentanyl.
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