Bromazepam chemical structure
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Bromazepam (marketed under brand names Compendium®, Creosedin®, Durazanil®, Lectopam®, Lexaurin®, Lexomil®, Lexotan®, Lexotanil®, Normoc®, Somalium®) is a drug which is a benzodiazepine derivative. It has sedative, hypnotic, anxiolytic and skeletal muscle relaxant properties. more...

Benzalkonium chloride


Its molecular structure is composed of a diazepine connected to two benzene rings, one of which has a bromine atom attached to it. It is a 1,4-benzodiazepine, which means that the nitrogens on the seven-sided diazepine ring are in the 1 and 4 positions.

Bromazepam binds to the GABA receptor GABAA, causing a conformational change and increasing inhibitory effects of GABA. Other neurotransmitters are not influenced. It does not possess any antidepressant qualities. Bromazepam shares with other benzodiazepines the risk of abuse, misuse, psychological and/or physical dependence. According to many psychiatric experts Bromazepam has a greater abuse potential than other benzodiazepines because of fast resorption and rapid onset of action. Due to its relatively short halflife and duration of action (8 to 12 hours), withdrawal symptoms may be more severe and more frequently encountered than with long acting benzodiazepines.

Bromazepam is reported to be metabolized by a hepatic enzyme belonging to the Cytochrome P450 family of enzymes. In 2003, a team led by Dr. Oda Manami at Oita Medical University reported that CYP3A4 was not the responsible enzyme, seeing as itraconazole, a known inhibitor of CYP3A4, did not effect its metabolism. In 1995, J. van Harten at Solvay Duphar B.V.'s Department of Clinical Pharmacology in Weesp reported that fluvoxamine, which is a potent inhibitor of CYP1A2, a less potent CYP3A4 inhibitor, and a negligible inhibitor of CYP2D6, does inhibit its metabolism.

The active metabolite of bromazepam is hydroxybromazepam.


  • Short-term treatment of insomnia
  • Short-term treatment of anxiety or panic attacks, if a benzodiazepine is required
  • Alleviation of the symptoms of alcohol- and opiate-withdrawal, under close clinical supervision


Bromazepam is available as a generic in Canada, Germany, Italy, France, Portugal, Switzerland, It is also available in the United Arab Emirates, Venezuela and Columbia in the form of Lexotanil and in Brazil and Portugal in the form of Lexotan.


Usually, 3mg to 6mg at bedtime, with additional 1.5mg to 3mg during the next day if needed. Malnourished patients, patients with compromised cardiovascular, liver or renal function, and elderly patients should receive lower doses. In hospitalized patients with severe agitation and/or anxiety, daily doses of up to 24mg have been given and tolerated for a limited period of time. A 3mg dose of bromazepam is equivalent to a 5mg dose of diazepam.


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Cerebral blood flow velocity alterations, under two different carbon dioxide management strategies, during sevoflurane anesthesia in gynecological laparoscopic
From Neurological Research, 6/1/03 by Papadimitriou, Lila S

In this study, 33 female patients, scheduled for operative gynecological laparoscopies, were enrolled. Our aim was prospective, randomized comparison of the influence of two different management strategies, regarding end tidal CO2, on cerebral blood flow velocities and on pulsatility index, examined by means of transcranial Doppler ultrasonography, under sevoflurane anesthesia 1.3 MAC: permissive hypercapnia (up to 45 mmHg, Group I, n =17) versus intervention to ensure mild hypocapnia, (around 33 mmHg, Group II, n=16). Baseline measurements of investigated parameters were recorded and CO2 insufflation started. In Group I no further adjustment was performed and CO2 partial pressure rose, while in Group II it was kept stable, by ventilatory patterns adjustment. Hemodynamic, acid base balance and cerebrovascular variables were recorded during pneumoperitoneum and in post-desufflation period, at eight checking time points. In Group I cerebral blood flow velocities increased according to CO2 elevation (2.3%-3.9% per mmHg of increase in CO2 partial pressure), whereas in Group II no significant alterations were noticed. Pulsatility index was constant over time without clinical differences between groups. Our study suggests that under sevoflurane anesthesia 1.3 MAC, prophylactic hyperventilation limits the cerebral blood flow velocities enhancing effect of CO2 insufflation, during laparoscopies. [Neurol Res 2003; 25: 361-369]

Keywords: Sevoflurane; CBFV; TCD; CO2 effects; pneumoperitoneum, laparoscopies


Laparoscopic surgery, for therapeutic and diagnostic purposes, has rapidly become a popular and widely used technique. In the recent years, it has been greatly developed and has also become standard as an operative procedure, due to the multiple benefits to the patients1-5.

Gynecological laparoscopies have also rapidly increased during the last few years and have gained worldwide acceptance, offering to female patients major medical and economical advantages over laparotomy6'7. Being relatively new surgical procedures, enjoying ever increasing popularity and presenting new anesthetic challenges, these techniques have advantages, such as smaller post-operative scars, decreased post-operative pain, earlier ambulation, shorter hospital stay, quicker post-operative recovery and minimized post-operative morbidity1,2,6,8. Nevertheless, even in operations of short duration, their benefits are partially offset by potential hazards, induced by CO2 insufflation1,2,8-13.

Many studies have focused on the effects of intraperitoneal CO2 insufflation on cardiovascular, respiratory and on acid base balance derangement, all being potentially able to impair cerebral perfusion1,14-6. The normal cerebrovascular response to CO2 alterations (CO2 reactivity) has already been analyzed profoundly17"20. In contrast, there are few reports about cerebrovascular dynamics alterations after CO2 insufflation into peritoneal cavity, during laparoscopies, and its effects on cerebral blood flow velocities (CBFV)21-25.

The effects on cerebral blood flow (CBF) of inhalation anesthesia depend on the balance between its indirect vasoconstrictive action, secondary to flow metabolism coupling and its intrinsic vasodilatory properties26,27. CO2 reactivity and autoregulation remain intact during sevoflurane administration at 0.5, 1.2 and 1.5 minimum alveolar concentration (MAC)28. Under a similar concentration (1.2 MAC), sevoflurane reduced middle cerebral artery mean velocity (MCA Vm) compared to the awake condition, while CO2 reactivity and autoregulation were well maintained, with or without nitrous oxide29. Data concerning comparison of CBF alterations, during sevoflurane anesthesia, at different levels of partial pressure of CO2, in gynecological laparoscopies, as a result of CO2 re-absorption via the exposed peritoneal surface area, are sparse in literature.

The aim of this prospective, randomized, clinical study was 1. to compare the influence of two different management strategies, regarding end tidal CO2 (EtCO^sub 2^), on CBFV and on pulsatility index (Pl), examined by means of transcranial Doppler ultrasonography (TCD), under sevoflurane anesthesia 1.3 MAC: permissive hypercapnia (up to 45 mmHg, Group I, n=17) versus intervention to ensure mild hypocapnia, (around 33 mmHg, Group II, n=16), during gynecological laparoscopies; 2. to correlate the above CBFV changes with partial pressure of arterial CO2 (PaCO^sub 2^) variations; and 3. to test the hypothesis that prophylactic hyperventilation limits the CBF enhancing effect of CO2 insufflation during laparoscopy


Thirty-three nonsmoking, female patients, scheduled for operative gynecological laparoscopies of standard duration, under sevoflurane anesthesia, 1.3 MAC, were enrolled in this prospective, randomized, clinical study. After institutional approval of our protocol by the Institutional Review Board and the Local Ethics Committee on Human Research and Human Studies of Aretaieion University Hospital (Athens, Greece), written informed consent was obtained from each patient preoperatively.

All patients were between 26 and 46 years of age and were in ASA physical status classification I and II. None of the patients suffered from any functionally limiting disease, either cardiovascular (including hypertension), respiratory, renal, hepatic, endocrine, metabolic or cerebrovascular (neurologic disease or recent head injury). In addition, pre-operatively, none had been receiving regularly any kind of chronic medication or was under vasoactive or psychoactive drugs. Preoperative electrocardiogram, chest roentgenogram and hematological findings were normal in all patients.

Patients were randomly allocated into two groups according to the levels of EtCO^sub 2^, using two different management strategies during the study. In Group I (n=17) EtCO^sub 2^ was allowed to rise, within safety limits, to levels of permitted hypercapnia (up to 45 mmHg), while in Group IIl(n=16), it was kept almost constant, to ensure mild hypocapnia by means of ventilatory patterns adjustment (around 33 mmHg).

All patients were given bromazepam 1.5 mg as standard pre-medication and ranitidine 150mg for gastric mucosa protection, both twice, peros, 10h and 1.5 h prior to anesthesia induction.

On arrival to the operating room intravenous access was established by insertion of an i.v. cannula (18G) for drug and fluid administration. Routine monitoring, including heart rate (HR), electrocardiogram lead II (ECG), noninvasive arterial blood pressure and systemic oxygen saturation through a pulse oximeter (SpO^sub 2^), was used, by means of Nihon Coden Life Scope 9 monitor (Tokyo, Japan). An i.v. infusion of Lactated Ringer's solution started prior to anesthesia induction, at a rate of 8 ml kg^sup -1^.

A standard anesthetic procedure was provided to all patients. While they were breathing 100% O2 (10lmin^sup -1^) through a face mask, sevoflurane was administered for the first 3 min at an inspired concentration of 8%. Initially the patients were encouraged to breathe normally, whereas, as soon as respiration became suppressed, they were manually ventilated, until the breathing circuit, the patients' functional residual capacity and their arterial circulation had been primed with the volatile agent. Endotracheal intubation (ETI) was facilitated with i.v. administration of rocuronium bromide (0.6mgkg^sup -1^) and adequate neuromuscular block during the whole procedure was maintained with a continuous i.v. infusion of rocuronium, at a rate of 5-12 meg kg^sup -1^ min^sup -1^. Anesthesia was maintained with sevoflurane, provided at 1.3 MAC (end-tidal concentration of sevoflurane approximately 2.6%), in O2/air mixture 50% (FiO^sub 2^ = 0.5). An i.v. infusion of remifentanil was commenced after ETI and was continued throughout the study (0.3 meg kg^sup -1^ min^sup -1^). Remifentanil was used to provide a rapidly variable level of opioid activity, to control arterial blood pressure in the face of any variation in surgical stimulation.

Prior to anesthesia induction, a radial artery catheter (20G) was inserted, under local anesthesia, to allow continuous direct invasive arterial blood pressure (IABP) monitoring (systolic, diastolic and mean arterial blood pressure SAP, DAP, MAP/Nihon Coden Life Scope 9 monitor), as well as for acquisition of repeated arterial blood gas sampling. The catheter was connected to a calibrated pressure transducer, zeroed at the level of the right atrium.

Controlled ventilation was instituted and initially adjusted in all patients, to maintain EtCO^sub 2^ around 33 mmHg for 20 min after ETI, in order to take baseline measurements. Ventilation was volume cycled, using a semi-closed circle system, incorporating a carbon dioxide absorber (Cicero respirator, Drager Corp, Luebeck, Germany). The ventilator was inspected for leaks before each case and the same type of disposable breathing tubing was used throughout the whole study period. End-tidal concentration of CO2 and sevoflurane were monitored continuously, using a dedicated infrared gas analyzer (Cicero respirator, Drager Corp.), which had been calibrated before initiation of the study. Temperature was monitored by an esophageal probe and maintained around 37[degrees]C, by regulating ambient temperature with hot water warming pads and warming blankets. All patients were placed in a light Trendelenbourg position (15[degrees] head down tilt), immediately after ETI and this position was maintained until the end of the study.

At the beginning of the study, prior to anesthesia induction, a TCD probe of 2 MHz pulse waves (TCD Nicolet Biomedical, EME Pioneer, CPN 169 414701) was positioned over the temporal bone window (the temporal area just above the zygomatic arch) and was anchored and fixed to the patient's forehead, at the site of best MCA insonation (depth 35-55 mm), using a specially designed frame, so that the insonation angle remained constant throughout the study, and had been giving continuously MCA velocities (peak systolic Vs, end diastolic Vd, mean Vm) and Pl. Time averaged MCA Vm and Pl were automatically calculated and monitored continuously by TCD (Pl = [Vs-Vd]/Vm). The values were obtained only during end expiration to avoid respiratory fluctuations and averaged over 3-4 cycles.

Under steady state conditions, as indicated by a stable hemodynamic and cerebrovascular profile, 20 min after ETI, CO2 insufflation started at a flow rate of 5.0 I min^sup -1^. Intra-abdominal pressure was maintained around 12 mmHg for 50 min in both groups. Afterwards, during the whole study period, in Group I no further adjustment of EtCO^sub 2^ was performed, while in Group II ventilatory patterns were altered to keep EtCO^sub 2^ almost constant and achieve target levels around 33 mmHg.

During the whole study period the following parameters were recorded and saved for later analysis: SAP, DAP, MAP, HR, SpO^sub 2^, Vs, Vd, Vm, Pl, EtCO^sub 2^, end-tidal sevoflurane concentration, peak airway pressure (Paw), esophageal temperature and arterial blood gas analysis [PaCO^sub 2^, PaO^sub 2^, SaO^sub 2^, HCO^sub 3^, pH] (ABL 300 Radiometer, Copenhagen). After baseline recordings (T0), all measurements were carried out at seven different time points (T1-T8) (Figure 1). Blood gas samples were withdrawn simultaneously to cardiovascular, respiratory and TCD recordings. End-tidal concentration of sevoflurane remained constant, approximately at 1.3 MAC, for 60 min, from baseline (T0) until 10 min after CO2 desufflation (T6).

Continuous data are expressed as mean value one standard deviation (SD). In order to evaluate potential differences in the investigated parameters we applied t-test, trend analysis and multiway analysis of variance. In addition, post hoc tests were carried out, performing all pairwise comparisons between checking time points of the analysis. The overall significant level (p-value) was calculated, based on Bonferroni's adjustment for multiple comparisons. A clinically significant alteration in hemodynamic variables was pre-determined as a 10% change from baseline values. A value of p


As shown in Table 1, no statistically significant differences were found between the study groups concerning their demographic and operative data.

Over the course of the study, hemodynamic variables' alterations by CO2 insufflation were clinically insignificant, ranging between 10% from baseline, at different checking time points and no vasoactive agents were needed (Group I, SAP: +1% to +7%, DAP: +1% to + 4%, MAP: +2% to +4% and HR: +4% to +7%, Group II, SAP: + 1 % to + 3%, DAP: 0% to + 3%, MAP: + 1% to + 3% and HR: + 1% to + 4%). Their changes over time remained within the clinically acceptable variation (+ or - 10%) from baseline levels, despite the fact that statistically significant but clinically insignificant differences have been found from the within-group and between-group analysis of variance (p

pH values revealed a decreasing tendency from baseline, at all checking time points, in both groups (Table 2). In Group I, this reduction was statistically significant during the whole duration of pneumoperitoneum, as well as during the post-desufflation period, whereas in Group II it begins to be significant only 20 min after CO2 insufflation (T2). Thus, concerning pH values, statistically significant differences from the between-group comparison appear to be evident from checking time point T1. pH remained reduced during the whole post-desufflation period in both groups, with significantly lower values in Group I. No statistically or clinically significant alterations were observed concerning PaO^sub 2^, SpO^sub 2^, SaO^sub 2^, or HCO^sub 3^ values throughout the whole study period, between groups and at different checking time points, within groups separately. Temperature remained steady between 36.6[degrees] and 37.3[degrees]C, during the whole procedure. Paw was in the range of 18-22 cm H2O in all patients.

PaCO^sub 2^ values fluctuated in both groups in accordance with EtCO^sub 2^ values (Table 2). In Group I, PaCO^sub 2^ increased at the end of pneumoperitoneum by 30.1% from baseline (p

The main findings of this study are depicted in Table 3 and Figure 2. During CO2 insufflation, MCA CBFV demonstrated a significant increase compared to baseline, in Group I from the beginning of pneumoperitoneum for Vs, Vd, Vm (checking time point T1) and in Group II 20 min after CO2 insufflation for Vd, Vm (T2) and 30 min after CO2 desufflation for Vs (T3). In the post-desufflation period MCA velocities continued to increase to higher values, in both groups, in comparison with baseline and pneumoperitoneum values (Figure 2). The statistical analysis (Table 3) showed a continuous increase of PaCO^sub 2^ in Group I, followed by a significant increase of Vs, Vd and Vm. In Group II, velocities showed a moderate rate of increase compared with Group I, during pneumoperitoneum (T1 T6), as well as in the post desufflation period (T7 T8) (Table 3). Pl was ranging from T0 to T8, in Group I from 0.6097 + or - 0.1108 to 0.7084 + or - 0.1492 (p 0.05).

The relationship between PaCO^sub 2^ and MCA Vm from baseline (T0) to T6 is presented in Figure 3. There was a significant positive correlation of PaCO^sub 2^ and Vm in Group I for the period of time referred above (r=0.870, p


In this study, it was found that, during gynecological laparoscopies, under sevoflurane anesthesia 1.3 MAC, prophylactic hyperventilation limits the CBF enhancing effect of CO2, normally expected, due to its intraperitoneal insufflation. MCA velocities increased in accordance with the elevation of PaCO^sub 2^, under administration of sevoflurane 1.3 MAC, in both groups, but in a more abrupt way in Group I than in Group II.

More specifically, during the whole study period, in Group I (permissive hypercapnia) Vm elevated from 62% to 64% in comparison with baseline values. In this Group, during administration of constant concentration of sevoflurane at 1.3 MAC (T0 T6), a 2.3%-3.9% change in Vm was observed for every mmHg of increase in PaCO^sub 2^, as it was calculated from the correlation regression analysis between Vm and PaCO^sub 2^. This is in accordance with the elevation (2.5%-5.0%) observed in awake patients17,18,30. In contrast, in Group II (mild hypocapnia), Vm increased from just 14% to 16%, compared to baseline. The later outcome may be attributed to the limited variation of EtCO^sub 2^ and PaCO^sub 2^ by design. From our results it was proved that the use of two different management strategies regarding EtCO^sub 2^, may result in different levels of increase of CBFV after induction of pneumoperitoneum, under sevoflurane anesthesia.

We chose to examine the effects of the above referred strategies on cerebral dynamics, under a constant end tidal concentration of sevoflurane of 1.3 MAC, to allow comparison with the already published data. Since MAC of sevoflurane was constant in both groups and blood pressure in the normotensive range, changes in MCA velocities can be attributed to changes in PaCO^sub 2^. Hence, one can conclude that sevoflurane was not responsible for the production of any significant change in MCA Vm, the main factor of interest, leaving it intact, in anesthetized patients under the same operative protocol.

With intraperitoneal CO2 insufflation, in Group I, PaCO^sub 2^ and MCA CBFV (Vs, Vd, Vm) increased significantly from baseline. In Group I there was a significant positive correlation between PaCO^sub 2^ and Vm during pneumoperitoneum (R= 0.87) and sometime after CO2 desufflation (T0-T6), while patients were still anesthetized under sevoflurane (constant end tidal concentration). This correlation, for the same period of time was very weak in Group II, where EtCO^sub 2^ remained almost stable. Hence, CO2 has more potently contributed in CBFV alterations than sevoflurane, which influenced Vm only slightly or not at all, since in Group II absence of elevated PaCO^sub 2^ correlated with absence of strongly disturbed CBFV.

Our findings are in agreement with the recently published reports on human cerebral circulation and CO2 reactivity during sevoflurane anesthesia. Although most volatile anesthetics cause cerebral vasodilation, as Cho and colleagues reported, 1.2 MAC of sevoflurane decreases cerebral blood flow velocities to less than awake values. They have also concluded that CO2 reactivity was well maintained during 1.2 MAC sevoflurane anesthesia, with and without nitrous oxide, in 14 volunteer patients, at three different levels of PaCO^sub 2^^sup 29^. Bedforth ef al.31 indicated that MCA Vm is not significantly altered by sevoflurane up to 3.4% in oxygen, and that under these conditions cerebral autoregulation and transient hyperemic response are also preserved. Heath ef al.32 concluded that in neurosurgical patients, sevoflurane at 0.5, 1.5 MAC has minimal effects on cerebral blood flow velocities, although this volatile anesthetic at an inspired concentration of 3% (large dose) was responsible for an observed reduction in brain oxygen consumption and an increase in flow metabolism ratio, thus providing a degree of luxury perfusion. Additionally, in common with other volatile agents, but to a lesser degree, sevoflurane up to 1.5 MAC has an intrinsic dose-dependent cerebral vasodilatory effect, resulting in an elevation of CBFV, but in a dose-dependent and time-dependent manner14. However, the magnitude of CBFV increase is significantly less than with equipotent anesthetic concentrations of other volatile agents, under similar conditions. This weak intrinsic cerebral vasodilatory action of sevoflurane leaves the cerebral vasculature capable of responding to changes in perfusion pressure and is unlikely responsible for a significant increase in intracranial pressure (ICP)33. This hypothesis has recently been supported by Artu ef al.34 who reported no increases in ICP during sevoflurane anesthesia 0.5, 1.0 and 1.5 MAC.

The above referred negligible alteration of CBFV, and thus CBF, under high concentrations of sevoflurane (above 1.5 MAC 3%) has been reported. In our study we did not provide high concentrations of this volatile anesthetic (up to 1.3 MAC, approximately 2.6%). Theoretically, sevoflurane might cause minimal increase in CBF and ICP at normocarbia. It could slightly dilate cerebral vessels and impair CBF in a dose dependent manner, but to a lower level than other volatile agents33,34. More specifically, equipotent anesthetic concentrations of sevoflurane and desflurane resulted in significantly greater MCA CBFV in those patients receiving desflurane, in comparison with those receiving sevoflurane35. Attempts to compare the level of increase of CBFV of sevoflurane versus isoflurane, both provided at 1 MAC, revealed greater vasodilatory properties attributed to isoflurane than to sevoflurane, at ETCO^sub 2^ values from 20 to 40 mmHg36.

It is accepted that inhalation anesthetics affect the cerebral vasculature in two opposite ways, in a dose-related fashion. As a group they are unique in that reduced cerebral blood flow due to cerebral vasoconstriction is an indirect effect of reduced cerebral metabolism in the presence of flow metabolism coupling. Cerebral vasodilation may be caused directly by the action of volatile anesthetics on vascular smooth muscle, reducing cerebrovascular resistance and increasing cerebral blood flow31,37. Thus, the net effect of inhaled anesthetics on CBF depends on the level of cerebral metabolism before the agent is added28. Nevertheless, in clinical practice, this net vasodilatory effect of volatile anesthetics can be attenuated by hyperventilation31,38. This was proved in our study, where prophylactic hyperventilation resulted in non-significant changes in CBFV.

CBF can be measured by several techniques. TCD, by measuring CBFV, can estimate CBF in an indirect way and has already been proved a quite accurate, noninvasive type of monitoring of CBFV in large cerebral arteries. Provided that the angle of insonation and the diameter of the vessel insonated (MCA) remain constant, corresponding changes in MCA CBFV accurately reflect relative concomitant changes in CBF39. By using special fixation to maintain the probe in position, it was ensured that the angle of insonation remained constant. There is also now ample direct and indirect evidence to support the view that the diameter of MCA does not change significantly with changes in PaCO^sub 2^ and blood pressure, or with use of anesthetics and vasoactive agents, since MCA, unlike arteriols, is a large conductive vessel39,40. Our study showed that EtCO^sub 2^ and PaCO^sub 2^ had parallel changes. In Group I, they increased significantly in comparison with baseline values, after CO2 insufflation, which is in agreement with previous investigations. The mechanism of hypercarbia presumably is peritoneal absorption of CO21,14. PaCO^sub 2^ influences CBF profoundly and hypercapnia causes intense cerebral vasodilatation and increase in CBF. Cerebral arteries and arterioles show quick response to the changes of PaCO^sub 2^. Hypercapnia exhausts the cerebral vasodilation response to changes in perfusion pressure and reduces autoregulatory capacity. On the contrary, hypocapnia increases cerebral vascular tone and results in improved cerebral autoregulation14. CO2 is a strong stimulus for vasodilation caused by vascular smooth muscle cell relaxation. Although the exact mechanism by which CO2 induces this relaxation is incompletely understood, evidence exists that it is predominantly mediated by a decrease in extracellular pH. Lowering the extracellular pH has been shown to cause vascular smooth muscle cell membrane hyperpolarization, activation of potassium channels and inactivation of calcium channels. These events may result in reduction of intracellular calcium level and a consecutive decrease of vascular tone41. This effect is almost immediate and is thought to be secondary to changes in the pH of the cerebrospinal fluid and cerebral tissue14.

Concerning autoregulation mechanisms, in this study we have not used autoregulatory tests. It has already been proved that sevoflurane 0.5, 1.2, 1.5 MAC does not influence this cerebral mechanism28,29. Kitaguchi et al.42 demonstrated that autoregulation is maintained during 0.88 MAC of sevoflurane in patients with ischmic cerebrovascular disease, undergoing extracranial intracranial bypass. Taking into account that hemodynamic variables in our study were not significantly altered, we can conclude that our results were not affected by variations of the cerebral autoregulatory mechanism.

Determination of the effects of specific anesthetics are complicated by the concomitant administration of other drugs, as well as by alterations of blood pressure and CO2 tension. The other drugs used during our study do not have direct vasodilatory effects. Remifentanil, when continuously infused, has been reported to leave MCA CBFV unchanged at 1 mcg kg^sup -1^ min^sup -1^, but to reduce them at 3 mcg kg^sup -1^ min^sup -1^43 . Furthermore, Ostapkovich et al.44 concluded that remifentanil given at a rate of 1 mcg kg^sup -1^ min^sup -1^ leaves cerebrovascular carbon dioxide reactivity intact, and that in anesthetized dogs it does not cause any vasodilation45. Additionally, in an open label trial, remifentanil did not appear to cause vasodilation or to impair patient responsiveness to carbon dioxide46. In our protocol remifentanil was provided at 0.3 mcg kg^sup -1^ min^sup -1^, in a quite low dose, unlikely impairing cerebral circulation.

Pl, an approximate indicator of cerebrovascular resistance, is an attempt to quantify the shape of TCD waveform. Generally, its increase indicates decreased compliance or increased intracranial pressure and increased peripheral resistance, and its reduction points to a decreased one, suggesting an ischmic flow pattern with a maximally dilated vessel. Our study showed significant Pl changes in Group I, but within the range of normal subjects. This indicates that the resistance of vessels distal to MCA remained almost intact, independently to PaCO^sub 2^ levels37,47. Although Pl is theoretically influenced by both Vs and Vd, in practice it has been noted to be less variable than these two parameters individually. The reason for this observation is uncertain48,49.

Finally, as shown by Figure 2, in both groups there was a continuous increase of CBFV after extubation, even 20 min after it, when patients were awake and calm, but in a more abrupt way in Group I versus Group II. We did not find any literature explaining such a phenomenon, but we believe that it must be related to the different intra-operative management strategies regarding end-tidal carbon dioxide, since it is the only different parameter between the two groups. Nevertheless, we do not have any proof determining whether sevoflurane, pneumoperitoneum or both were responsible for this delayed remaining elevation. As such, it is suggested that more trials are needed to be performed, in order to elucidate all the CBFV alterations happening after awakening patients from surgical procedures under sevoflurane anesthesia.


The study demonstrated that CO2 insufflation into the peritoneal cavity during sevoflurane anesthesia 1.3 MAC, in gynecological laparoscopies, in head down tilt, has negligible effect on cerebral hemodynamics, such as CBFV, with the presupposition that EtCO^sub 2^ is adjusted around mild hypocapnic levels. This study also supports that during laparoscopic surgery, carbon dioxide elevation strongly correlates with the increase of CBFV and that hyperventilation attenuates the CO2 cerebral vasodilating properties. The cerebrovascular system can undergo adaptive changes during laparoscopies. It is recommended to anticipate any increase in CBFV after CO2 insufflation, by adjusting ventilatory patterns from the beginning, so that EtCO^sub 2^ is kept around 33 mmHg, in mild hypocapnic levels, in order to minimize the potential negative effects of pneumoperitoneum, hemodynamic fluctuations and inhalation anesthesia on cerebrovascular balance. Clearly, further studies are needed to enlighten the necessary measures for preventing possible alteration of CBFV during specific operations in Trendelenbourg position, especially in patients with cardiovascular and cerebral derangement.


1 Morgan EC, Mikhail MS. Anesthesia for patients with respiratory disease. In: Morgan EG, Mikhail MS, eds. Clinical Anesthesiology, 2nd edn, Stamford: Appleton and Lange, 1996: pp 450-452

2 Grant IS, Nimmo GR. Intercurrent disease and anaesthesia. In: Aitkenhead AR, Rowbotham DJ, Smith G, eds. Textbook of Anaesthesia, 4th edn, Edinburgh: Churchill Livingstone, 2001; pp 437-438

3 Cunningham AJ, Brull SJ. Laparoscopic cholocystectomy: Anesthetic implications. Anesth Analg 1993; 76: 1120-1133

4 Cunningham AJ. Laparoscopic surgery - anesthetic implications. Surg Endosc 1994; 8: 1272-1284

5 Horgan PG, Fitzpatrick M, Couse NF, et al. Laparoscopy is less immunotraumatic than laparotomy. Min Invas Ther 1992; 1: 241-244

6 Ohlgisser M, Sorokin Y, Heifetz M. Gynecologic laparoscopy. A review article. Obstet Gynecol Surv 1985; 40: 385-396

7 Langebrekke A, Skar O, Urnes A. Laparoscopic hysterectomy. Initial experience. Acta Obstet Gynecol Scand 1992; 71: 226-229

8 Schleifer W, Bissinger U, Guggenberger H, et al. Variance of cardiorespiratory parameters during gynecological surgery with CO2 pneumoperitoneum. End Surg 1995; 3: 167-170

9 Calverley RK, Jenkins LC. The anesthetic management of pelvic laparoscopy. Can Anaesth Soc J 1973; 20: 679-686

10 Tan PL, Lee TL, Tweed W. Carbon dioxide absorption and gas exchange during pelvic laparoscopy. Can J Anaesth 1992; 39: 677-681

11 Ishizaki Y, Bandai Y, Shimomura K, et al. Changes in splachnic blood flow and cardiovascular effects following peritoneal insufflation of carbon dioxide. Surg Endosc 1993; 7: 420-423

12 Querleu D, Chapron C. Complications of gynecologic laparoscopic surgery. Curr Opin Obstet Gynecol 1995; 7: 257-261

13 Casati A, Valentini G, Ferrari S, et al. Cardiorespiratory changes during gynecological laparoscopy by abdominal wall elevation: Comparison with carbon dioxide pneumoperitoneum. Br J Anaesth 1997; 78: 51-54

14 Morgan EG, Mikhail MS. Neurophysiology and Anesthesia. In: Morgan EG, Mikhail MS, eds. Clinical Anesthesiology, 2nd edn, Stamford: Appleton and Lange, 1996: pp 477-490

15 Iwasaka H, Miyakawa H, Yamamoto H, et al. Respiratory mechanics and arterial blood gases during and after laparoscopic cholocystectomy. Can J Anaesth 1996; 43: 129-133

16 Couture P, Boudreault D, Gigard F, et al. Haemodynamic effects of mechanical peritoneal retraction during laparoscopic cholocystectomy. Can J Anaesth 1997; 44: 467-472

17 Markwalder TM, Grolimund P, Seiler RW, et al. Dependency of blood flow velocity in the middle cerebral artery on end tidal carbon dioxide partial pressure: A transcranial ultrasound Doppler study. J Cereb Blood Flow Metab 1984; 4: 368-372

18 Kirkham FJ, Padayachee TS, Parsons S, et al. Transcranial measurement of blood velocities in the basal cerebral arteries using pulsed Doppler ultrasound velocity: Velocity as an index of flow. Ultrasound Med Biol 1986; 12: 15-21

19 Dahl A, Lindegaard KF, Russell D, et al. A comparison of transcranial Doppler and cerebral blood flow studies to assess cerebral vasoreactivity. Stroke 1992; 23: 15-19

20 Nishiyama M, Sugai N, Hanaoka K. Cerebrovascular CO2 reactivity in elderly and younger adult patients during sevoflurane anaesthesia. Can J Anaesth 1997; 44: 160-164

21 Fujii Y, Tanaka H, Tsuruoka S, et al. Middle cerebral arterial blood flow velocity increases during laparoscopic cholocystectomy. Anesth Analg 1994; 78: 80-83

22 Kirkinen P, Hirvonen E, Kauko M, et al. lntracranial blood flow during laparoscopic hysterectomy. Acta Obstet Gynecol Scand 1995; 74: 71-74

23 De Cosmo G, Lannace E, Primieri P, et al. Changes in cerebral hemodynamics during laparoscopic cholocystectomy. Neurol Res 1999; 21: 658-660

24 Abe K, Hashimoto N, Taniguchi A, et al. Middle cerebral artery blood flow velocity during laparoscopic surgery in head down position. Surg Laparosc and Enclose 1998; 8: 1-4

25 Josephs LG, Este McDonald JR, Birkett DH, et al. Diagnostic laparoscopy increases intracranial pressure. J Trauma 1994; 36: 815-819

26 Drumond JC, Todd MM, Scheller MS, et al. A comparison of the direct cerebral vasodilating potencies of halothane and isoflurane in the New Zeland white rabbit. Anesthesiology 1986; 65: 462-467

27 Lam A, Matta B, Mayberg T, et al. Changes in cerebral blood flow velocity with onset of EEG silence during inhalational anesthesia in humans: Evidence of flow metabolism coupling. J Cereb Blood Flow Metab 1994; 15: 714-717

28 Gupta S, Heath K, Matta B. Effect of incremental doses of sevoflurane on cerebral pressure autoregulation in humans. Br J Anaesth 1997; 79: 469-472

29 Cho S, Fujigaki T, Uchiyama Y, et al. Effects of sevoflurane with and without nitrous oxide on human cerebral circulation. Anesthesiology 1996; 85: 755-760

30 Ringelstein EB, Sievers C, Ecker S, et al. Non invasive assessment of CO2 induced cerebral vasomotor response in normal individuals and patients with internal carotid artery occlusions. Stroke 1988; 19: 963-969

31 Bedforth N, Girling K, Harrison J, et al. The effects of sevoflurane and nitrous oxide on middle cerebral artery blood flow velocity and transient hyperemic response. Anesth Analg 1999; 89: 170-174

32 Heath K, Gupta S, Matta B. The effects of sevoflurane on cerebral hemodynamics during propofol anesthesia. Anesth Analg 1997; 85: 1284-1287

33 Matta B, Heath K, Tipping K, et al. Direct cerebral vasodilatory effects of sevoflurane and isoflurane. Anesthesiology 1999; 91: 677-680

34 Artru AA, Lam AM, Johnson JO, et al. lntracranial pressure, middle cerebral artery flow velocity and inorganic fluoride concentrations in neurosurgical patients receiving sevoflurane or isoflurane. Anesth Analg 1997; 85: 587-592

35 Bedforth NM, Hardman JC, Nathanson MH. Cerebral hemodynamic response to the introduction of desflurane: A comparison with sevoflurane. Anesth Analg 2000; 91: 152-155

36 Nishiyama T, Matsukawa T, Yokoyama T, et al. Cerebrovascular carbon dioxide reactivity during general anesthesia: A comparison between sevoflurane and isoflurane. Anesth Analg 1999; 89: 1437-1441

37 Hansen TD, Warner DS, Todd MM, et al. The role of cerebral metabolism in determining the local cerebral blood flow effects of volatile anesthetics: Evidence for persistent flow metabolism coupling. J Cereb Blood Flow Metab 1989; 9: 323-328

38 Huffman WE, Charbel FT, Edelman G, et al. Nitrous oxide added to isoflurane increases brain artery blood flow and low frequency brain electrical activity. J Neurosurg Anesthesiol 1995; 7: 82-88

39 Bishop CCR, Powell S, Rutt D, et al. Transcranial Doppler measurement of the middle cerebral flow velocity: A validation study. Stroke 1986; 17: 913-915

40 Newell WD, Aaslid R, Earn AM, et al. Comparison of flow and velocity during dynamic autoregulating testing in humans. Stroke 1994; 25: 793-797

41 Pfefferkorn T, Von Stuckrad-Barre S, Herzog J, et al. Reduced cerebrovascular CO2 reactivity in CADASIL. A transcranial Doppler sonography study. Stroke 2001; 32: 17-21

42 Kitaguchi K, Oshumi H, Kuro M, et al. Effects of sevoflurane on cerebral circulation and metabolism in patients with ischmic cerebrovascular disease. Anesthesiology 1993; 79: 704-709

43 Paris A, Scholz J, Von Knobelsdorff G, et al. The effect of remifentanyl on cerebral blood flow velocity. Anesth Analg 1998; 87: 569-573

44 Ostapkovich ND, Baker KZ, Fogarty-Mack P, et al. Cerebral blood flow and CO2 reactivity is similar during remifentanil/N^sub 2^O and fentanyl/N^sub 2^O anesthesia. Anesthesiology 1998; 89: 358-363

45 Baker KZ, Ostapkovich ND, Sisti MB, et al. Intact cerebral blood flow reactivity during remifentanil/nitrous oxide anesthesia. J Neurosurg Anesth 1997; 9: 134-140

46 Hoffman WE, Cunningham F, James MK, et al. Effects of remifentanil, a new short acting opioid, on cerebral blood flow, brain electrical activity and intracranial pressure in dogs anesthetized with isoflurane and nitrous oxide. Anesthesiology 1993; 79: 107-113

47 Tong D, Albers G. Normal values. In: Babikian V, Wechsler L, eds. Transcranial Doppler ultrasound, 2nd edn. Boston: Butterworth and Heinemann, 1999: pp 33-48

48 Lindegaard KF, Grolimund P, Aaslid R, et al. Evaluation of AVMs using transcranial Doppler ultrasound. J Neurosurg 1986; 65: 335-344

49 Czosnyka M, Richards HK, Whitehouse HE, et al. Relationship between transcranial Doppler determined pulsatility index and cerebrovascular resistance: An experimental study. J Neurosurg 1996; 84: 79-84

Lila S. Papadimitriou*, Stavros H. Livanios[dagger], Eleni G. Moka*, Theano D. Demesticha* and John D. Papadimitriou[double dagger]

*Anesthesiology Unit, [double dagger]2nd Surgical Clinic, Aretaieion University Hospital, University of Athens, Athens 8[dagger]Department of Anesthesia, Pediatric Hospital of Penteli, Athens, Greece

Correspondence and reprint requests to: Lila S. Papadimitriou, Assoc. Prof. Anesthesiology, University of Athens, 8, lassiou St., Kolonaki 11521, Greece, [] Accepted for publication November 2002.

Copyright Forefront Publishing Group Jun 2003
Provided by ProQuest Information and Learning Company. All rights Reserved

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