All benzodiazepines produce similar pharmacologic activity (eg, amnestic, anxiolytic, sedative-hypnotic) with their effects mediated by the same receptor (γ-aminobutyric acid), but there are some differences in pharmacokinetic properties (Table 2).35 The 2 most frequently used benzodiazepines are midazolam and lorazepam. Midazolam is highly lipophilic and has a rapid distribution into the central nervous system (CNS) and adipose tissue, resulting in rapid onset of action (<2.5 min).35 The rapid redistribution of the drug from the brain to peripheral tissues and a short half-life produce a rapid recovery.36 However, in patients with decreased clearance and/or when drug accumulates in adipose tissue prolonged sedation may result.35,36 Because of its lower lipophilicity and longer half-life, lorazepam has a slower onset of action (15 to 20 min) and a longer duration.35
The anterograde amnestic effect of benzodiazepines was demonstrated in a placebo-controlled trial of oral lorazepam as a premedication for bronchoscopy.2 In the immediate postprocedure period, there was no significant difference in patient perception between those receiving lorazepam and placebo-treated patients. However, 24 hours later, those in the lorazepam group were more likely to rate the procedure as “easy” and to be willing to undergo a second bronchoscopy.
One advantage of benzodiazepines is the availability of a competitive benzodiazepine receptor antagonist (flumazenil) to reverse the CNS depressant effects of these drugs and aid in recovery. In controlled trials, flumazenil successfully reversed benzodiazepine-induced sedation in patients undergoing bronchoscopy, and it may be effective for reversing benzodiazepine-induced hypoxia.11,58 However, because flumazenil has a shorter duration of action than benzodiazepines, there is the potential for relapse necessitating a second dose of the drug.11
Benzodiazepines are often used in combination with opioids because of the synergistic activity between these drug classes.35 These regimens can reduce the requirement for local anesthesia and provide a better antitussive effect.14,26,27,49,61 In randomized studies, the addition of an opioid to intravenous midazolam was associated with a significant reduction in cough and increased patient tolerance when compared with midazolam alone.14,49 In 1 study, there was a nonstatistically significant trend toward a decrease in the requirement for supplemental lidocaine with combination therapy.49
Like other sedative agents, benzodiazepines can produce cardiopulmonary depression. In a comparative trial with propofol, midazolam was associated with significantly higher heart rate and systolic blood pressure during the bronchoscopy when at the level of the vocal cords.15 Although low to moderate doses of midazolam (ie, <5 mg) do not seem to increase the risk of hypoxemia during flexible bronchoscopy, hypoxemia can occur with or without sedation.62 Another potential disadvantage of benzodiazepines is a prolonged effect with repeat dosing owing to drug accumulation in adipose tissue.35
Opioids have both sedative and analgesic effects. The most frequently used opioids are fentanyl and meperidine. Morphine sulfate is the least commonly used opioid.7 Because of synergistic activity, these agents are often used in combination with a benzodiazepine for moderate sedation.35 As with benzodiazepines, the availability of an opiate antagonist (ie, naloxone) is important to reverse the untoward side effects of opioids.16
The primary safety concern with opioids is respiratory depression, although most comparisons of single-agent regimens have not demonstrated a significant difference in hypoxemia between opioids and benzodiazepines.13,14,45,59 Risk of hypoxemia is enhanced when opioids are combined with other sedatives. In 1 randomized trial, oxygen saturation fell significantly more in patients receiving alfentanyl plus midazolam compared with those receiving alfentanyl alone.14
Opioids effectively blunt cardiovascular responses (eg, hypertension, tachycardia) that occur during mechanical stimulation of laryngeal and tracheal tissues. However, there is a risk of inducing hypotension with these agents.50 One small study suggested that remifentanil was more effective than fentanyl for preventing intraoperative hypertension and tachycardia and lowered the requirement for propofol for maintenance of anesthesia in patients undergoing rigid bronchoscopy.51
Fospropofol disodium (Aquavan Injection, MGI Pharma, Inc, Bloomington, MN) is a novel sedative/hypnotic, water-soluble prodrug of propofol with pharmacokinetic and pharmacodynamic properties that differ from those of propofol emulsion.17,18,39,67 After intravenous administration, propofol is released from the prodrug by enzymatic action, resulting in a predictable and controlled release of propofol.18,39 Compared with the conventional formulation of propofol, the plasma concentration profile of fospropofol is characterized by lower peak concentrations and a more gradual decline in propofol concentrations.18
In patients undergoing colonoscopy, fospropofol has demonstrated satisfactory depth and duration of sedation.68 A phase 3, randomized, double-blind, dose-controlled study in 252 patients to evaluate the efficacy and safety of fospropofol after pretreatment with fentanyl in patients undergoing flexible bronchoscopy has recently concluded with final analysis underway. Primary end points of sedation success and also secondary end points were met during the study.
Because of age-related decline in lung function, increased sensitivity to sedative drugs, and an increase in sedation-related adverse events, caution is warranted when administering sedation during bronchoscopy in the elderly.45,80 Elderly patients generally require smaller doses of sedative agents80 owing to prolonged time to recovery and increased amnestic effects of benzodiazepines in this patient population.53 In a study of patients over 75 years of age, temazepam plus nebulized lidocaine was associated with less coughing and better patient satisfaction with a trend toward less hypoxemia compared with alfentanyl alone.45 Doses of sedative agents should be titrated carefully and these patients should be closely monitored both during and after the procedure.
Sedatives used in children are generally similar to those used in adults, although the amnestic, analgesic, and dissociative properties of ketamine allow better control of the procedure.81 In addition, some advocate the use of inhalational anesthetics due to fear of needles by most children.82
1. Poi PJ, Chuah SY, Srinivas P, et al. Common fears of patients undergoing bronchoscopy
. Eur Respir J. 1998;11:1147–1149.
2. Maltais F, Laberge F, Laviolette M. A randomized, double-blind, placebo-controlled study of lorazepam as premedication for bronchoscopy
. Chest. 1996;109:1195–1198.
3. Maguire GP, Rubinfeld AR, Trembath PW, et al. Patients prefer sedation
for fibreoptic bronchoscopy
. Respirology. 1998;3:81–85.
4. Putinati S, Ballerin L, Corbetta L, et al. Patient satisfaction with conscious sedation
. Chest. 1999;115:1437–1440.
5. Gonzalez R, De-La-Rosa-Ramirez I, Maldonado-Hernandez A, et al. Should patients undergoing a bronchoscopy
be sedated? Acta Anaesthesiol Scand. 2003;47:411–415.
6. McLean AN, Semple PA, Franklin DH, et al. The Scottish multi-centre prospective study of bronchoscopy
for bronchial carcinoma and suggested audit standards. Respir Med. 1998;92:1110–1115.
7. Prakash UB, Offord KP, Stubbs SE. Bronchoscopy
in North America: the ACCP survey. Chest. 1991;100:1668–1675.
8. Pickles J, Jeffrey M, Datta A, et al. Is preparation for bronchoscopy
optimal? Eur Respir J. 2003;22:203–206.
9. Smyth CM, Stead RJ. Survey of flexible fibreoptic bronchoscopy
in the United Kingdom. Eur Respir J. 2002;19:458–463.
10. Shelley MP, Wilson P, Norman J. Sedation
for fibreoptic bronchoscopy
. Thorax. 1989;44:769–775.
11. Shannon M, Albers G, Burkhart K, et al. Safety and efficacy of flumazenil in the reversal of benzodiazepine-induced conscious sedation
. The Flumazenil Pediatric Study Group. J Pediatr. 1997;131:582–586.
12. Williams T, Brooks T, Ward C. The role of atropine premedication in fiberoptic bronchoscopy
using intravenous midazolam sedation
. Chest. 1998;113:1394–1398.
13. Houghton CM, Raghuram A, Sullivan PJ, et al. Pre-medication for bronchoscopy
: a randomised double blind trial comparing alfentanil with midazolam
. Respir Med. 2004;98:1102–1107.
14. Greig JH, Cooper SM, Kasimbazi HJ, et al. Sedation
for fibre optic bronchoscopy
. Respir Med. 1995;89:53–56.
15. Ozturk T, Cakan A, Gulerce G, et al. Sedation
for fiberoptic bronchoscopy
: fewer adverse cardiovascular effects with propofol
than with midazolam
. Anasthesiol Intensivmed Notfallmed Schmerzther. 2004;39:597–602.
16. Greenwald B. Narcan use in the endoscopy lab: an important component of patient safety. Gastroenterol Nurs. 2004;27:20–21.
17. Struys MM, Vanluchene AL, Gibiansky E, et al. AQUAVAN injection, a water-soluble prodrug of propofol
, as a bolus injection: a phase I dose-escalation comparison with DIPRIVAN (part 2): pharmacodynamics and safety. Anesthesiology. 2005;103:730–743.
18. Gibiansky E, Struys MM, Gibiansky L, et al. AQUAVAN injection, a water-soluble prodrug of propofol
, as a bolus injection: a phase I dose-escalation comparison with DIPRIVAN (part 1): pharmacokinetics. Anesthesiology. 2005;103:718–729.
19. Berkenbosch JW, Graff GR, Stark JM. Safety and efficacy of ketamine sedation
for infant flexible fiberoptic bronchoscopy
. Chest. 2004;125:1132–1137.
20. Matot I, Kramer MR. Sedation
in outpatient bronchoscopy
. Respir Med. 2000;94:1145–1153.
21. Society AT. Flexible endoscopy of the pediatric airway. Am Rev Repir Dis. 1992;145:233–235.
22. Colt HG, Morris JF. Fiberoptic bronchoscopy
without premedication. A retrospective study. Chest. 1990;98:1327–1330.
23. Sutherland FW. Sedation
in fibreoptic bronchoscopy
. Intravenous sedation
is inappropriate in most minor procedures. BMJ. 1995;310:872.
24. Banerjee A, Banerjee SN, Nachiappan M. Premedication for fibreoptic bronchoscopy
a must?). Indian J Chest Dis Allied Sci. 1986;28:76–80.
25. Hatton MQ, Allen MB, Vathenen AS, et al. Does sedation
help in fibreoptic bronchoscopy
? BMJ. 1994;309:1206–1207.
26. Aslam M, Beg M. Desirability of using buprenorphine and diazepam as an adjunct to atropine in patients undergoing fibreoptic bronchoscopy
. J Pak Med Assoc. 1993;43:120–122.
27. Diette GB, Lechtzin N, Haponik E, et al. Distraction therapy with nature sights and sounds reduces pain during flexible bronchoscopy
: a complementary approach to routine analgesia
. Chest. 2003;123:941–948.
28. Honeybourne D, Babb J, Bowie P, et al. British Thoracic Society guidelines on diagnostic flexible bronchoscopy
. Thorax. 2001;56(suppl 1):i1–i21.
29. Wood-Baker R, Burdon J, McGregor A, et al. Fibre-optic bronchoscopy
in adults: a position paper of The Thoracic Society of Australia and New Zealand. Intern Med J. 2001;31:479–487.
30. Wood M. Variability of human drug response. Anesthesiology. 1989;71:631–634.
31. Gourlay GK, Kowalski SR, Plummer JL, et al. Fentanyl
blood concentration-analgesic response relationship in the treatment of postoperative pain. Anesth Analg. 1988;67:329–337.
32. Buhrer M, Maitre PO, Crevoisier C, et al. Electroencephalographic effects of benzodiazepines. II. Pharmacodynamic modeling of the electroencephalographic effects of midazolam
and diazepam. Clin Pharmacol Ther. 1990;48:555–567.
33. Mould DR, DeFeo TM, Reele S, et al. Simultaneous modeling of the pharmacokinetics and pharmacodynamics of midazolam
and diazepam. Clin Pharmacol Ther. 1995;58:35–43.
34. Shafer SL, Varvel JR. Pharmacokinetics, pharmacodynamics, and rational opioid selection. Anesthesiology. 1991;74:53–63.
35. Horn E, Nesbit SA. Pharmacology and pharmacokinetics of sedatives and analgesics. Gastrointest Endosc Clin N Am. 2004;14:247–268.
36. Fragen RJ. Pharmacokinetics and pharmacodynamics of midazolam
given via continuous intravenous infusion in intensive care units. Clin Ther. 1997;19:405–419. Discussion 367–408.
37. Tegeder I, Lotsch J, Geisslinger G. Pharmacokinetics of opioids in liver disease. Clin Pharmacokinet. 1999;37:17–40.
38. Kanto J, Gepts E. Pharmacokinetic implications for the clinical use of propofol
. Clin Pharmacokinet. 1989;17:308–326.
39. Fechner J, Ihmsen H, Hatterscheid D, et al. Pharmacokinetics and clinical pharmacodynamics of the new propofol
prodrug GPI 15715 in volunteers. Anesthesiology. 2003;99:303–313.
40. Persson J, Hasselstrom J, Maurset A, et al. Pharmacokinetics and non-analgesic effects of S- and R-ketamines in healthy volunteers with normal and reduced metabolic capacity. Eur J Clin Pharmacol. 2002;57:869–875.
41. Greenblatt DJ. Clinical pharmacokinetics of oxazepam and lorazepam. Clin Pharmacokinet. 1981;6:89–105.
42. Mather LE, Meffin PJ. Clinical pharmacokinetics of pethidine. Clin Pharmacokinet. 1978;3:352–368.
43. Driessen JJ, Smets MJ, Goey LS, et al. Comparison of diazepam and midazolam
as oral premedicants for bronchoscopy
under local anesthesia. Acta Anaesthesiol Belg. 1982;33:99–105.
44. Korttila K, Tarkkanen J. Comparison of diazepam and midazolam
during local anaesthesia for bronchoscopy
. Br J Anaesth. 1985;57:581–586.
45. Watts MR, Geraghty R, Moore A, et al. Premedication for bronchoscopy
in older patients: a double-blind comparison of two regimens. Respir Med. 2005;99:220–226.
46. Randell T. Sedation
for bronchofiberoscopy: comparison between propofol
infusion and intravenous boluses of fentanyl
and diazepam. Acta Anaesthesiol Scand. 1992;36:221–225.
47. Clarkson K, Power CK, O'Connell F, et al. A comparative evaluation of propofol
as sedative agents in fiberoptic bronchoscopy
. Chest. 1993;104:1029–1031.
48. Crawford M, Pollock J, Anderson K, et al. Comparison of midazolam
in outpatient bronchoscopy
. Br J Anaesth. 1993;70:419–422.
49. Stolz D, Chhajed PN, Leuppi JD, et al. Cough suppression during flexible bronchoscopy
using combined sedation
and hydrocodone: a randomised, double blind, placebo controlled trial. Thorax. 2004;59:773–776.
50. Kestin IG, Chapman JM, Coates MB. Alfentanil used to supplement propofol
infusions for oesophagoscopy and bronchoscopy
. Anaesthesia. 1989;44:994–996.
51. Voyagis GS, Dimitriou V. Remifentanil vs. fentanyl
during rigid bronchoscopy
under general anaesthesia with controlled ventilation. Eur J Anaesthesiol. 2000;17:404–405.
52. Hwang J, Jeon Y, Park HP, et al. Comparison of alfetanil and ketamine in combination with propofol
for patient-controlled sedation
during fiberoptic bronchoscopy
. Acta Anaesthesiol Scand. 2005;49:1334–1338.
53. Korttila K, Saarnivaara L, Tarkkanen J, et al. Effect of age on amnesia and sedation
induced by flunitrazepam during local anaesthesia for bronchoscopy
. Br J Anaesth. 1978;50:1211–1218.
54. Baktai G, Szekely E, Marialigeti T, et al. Use of midazolam
(‘Dormicum’) and flumazenil (‘Anexate’) in paediatric bronchology. Curr Med Res Opin. 1992;12:552–559.
55. Williams TJ, Bowie PE. Midazolam sedation
to produce complete amnesia for bronchoscopy
: 2 years' experience at a district general hospital. Respir Med. 1999;93:361–365.
56. Breuer HW, Charchut S, Worth H. Effects of diagnostic procedures during fiberoptic bronchoscopy
on heart rate, blood pressure, and blood gases. Klin Wochenschr. 1989;67:524–529.
57. Hewitt JM, Barr AM. Premedication with lorazepam for bronchoscopy
under general anaesthesia. Br J Anaesth. 1978;50:1149–1154.
58. Williamson BH, Nolan PJ, Tribe AE, et al. A placebo controlled study of flumazenil in bronchoscopic procedures. Br J Clin Pharmacol. 1997;43:77–83.
59. Papagiannis A, Smith AP. Fentanyl
as premedication for fibre optic bronchoscopy
. Respir Med. 1994;88:797–798.
60. Williams TJ, Nicoulet I, Coleman E, et al. Safety and patient acceptability of intravenous midazolam
for fibre optic bronchoscopy
. Respir Med. 1994;88:305–307.
61. Wong KS, Lan RS, Lin TY. Pediatric flexible bronchoscopy
: a three-year experience. Zhonghua Min Guo Xiao Er Ke Yi Xue Hui Za Zhi. 1995;36:257–260.
62. Jones AM, O'Driscoll R. Do all patients require supplemental oxygen during flexible bronchoscopy
? Chest. 2001;119:1906–1909.
63. Soifer BE. Procedural anesthesia at the bedside. Crit Care Clin. 2000; 16:7–28.
64. Gan TJ. Pharmacokinetic and pharmacodynamic characteristics of medications used for moderate sedation
. Clin Pharmacokinet. 2006;45:855–869.
65. Erb T, Hammer J, Rutishauser M, et al. Fibreoptic bronchoscopy
in sedated infants facilitated by an airway endoscopy mask. Paediatr Anaesth. 1999;9:47–52.
66. Moerman AT, Struys MM, Vereecke HE, et al. Remifentanil used to supplement propofol
does not improve quality of sedation
during spontaneous respiration. J Clin Anesth. 2004;16:237–243.
67. Fechner J, Ihmsen H, Hatterscheid D, et al. Comparative pharmacokinetics and pharmacodynamics of the new propofol
prodrug GPI 15715 and propofol
emulsion. Anesthesiology. 2004;101:626–639.
68. Cohen LWC, Jones JB. AQUAVAN is safe and effective for minimal to moderate sedation
during colonoscopy [abstract]. Anesthesiology. 2006;105:A1367.
69. Sikharam S, Egan TD, Kern SE. Cyclodextrins as new formulation entities and therapeutic agents. Curr Opin Anaesthesiol. 2005;18:392–395.
70. Egan TD, Kern SE, Johnson KB, et al. Propofol
in a modified cyclodextrin formulation: first in man pharmacodynamics. Anesth Analg. 2006;102:S297.
71. Law AK, Ng DK, Chan KK. Use of intramuscular ketamine for endoscopy sedation
in children. Pediatr Int. 2003;45:180–185.
72. Xie H, Wang X, Liu G, et al. Analgesic effects and pharmacokinetics of a low dose of ketamine preoperatively administered epidurally or intravenously. Clin J Pain. 2003;19:317–322.
73. Callahan CW. Chloral hydrate and sleep deprivation for sedation
during flexible fiberoptic bronchoscopy
. Pediatr Pulmonol. 1997;24:302.
74. Tobias JD. Sedation
in paediatric intensive care units: a guide to drug selection and use. Paediatr Drugs. 1999;1:109–126.
75. Bahhady IJ, Ernst A. Risks of and recommendations for flexible bronchoscopy
in pregnancy: a review. Chest. 2004;126:1974–1981.
76. Djukanovic R, Wilson JW, Lai CK, et al. The safety aspects of fiberoptic bronchoscopy
, bronchoalveolar lavage, and endobronchial biopsy in asthma. Am Rev Respir Dis. 1991;143:772–777.
77. Humbert M, Robinson DS, Assoufi B, et al. Safety of fibreoptic bronchoscopy
in asthmatic and control subjects and effect on asthma control over two weeks. Thorax. 1996;51:664–669.
78. Dransfield MT, Garver RI, Weill D. Standardized guidelines for surveillance bronchoscopy
reduce complications in lung transplant recipients. J Heart Lung Transplant. 2004;23:110–114.
79. Kurland G, Noyes BE, Jaffe R, et al. Bronchoalveolar lavage and transbronchial biopsy in children following heart-lung and lung transplantation. Chest. 1993;104:1043–1048.
80. Hehn BT, Haponik E, Rubin HR, et al. The relationship between age and process of care and patient tolerance of bronchoscopy
. J Am Geriatr Soc. 2003;51:917–922.
81. Slonim AD, Ognibene FP. Amnestic agents in pediatric bronchoscopy
. Chest. 1999;116:1802–1808.
82. Stacey S, Hurley E, Bush A. Sedation
for pediatric bronchoscopy
. Chest. 2001;119:316–317.
83. Brimacombe J, Berry A. Guidelines for care during bronchoscopy
. Thorax. 1994;49:528.
84. Gilbertson LI. Conscious sedation
in special settings. Int Anesthesiol Clin. 1999;37:123–129.
85. Thomas G, McBeth C. Sedation
in fibreoptic bronchoscopy
. Patients must be monitored. BMJ. 1995;310:872–873.
86. Tobias JD. Sedation
and anesthesia for pediatric bronchoscopy
. Curr Opin Pediatr. 1997;9:198–206.