The Effect of Nitrous Oxide on Jugular Bulb Oxygen Saturation During Remifentanil Plus Target-Controlled Infusion Propofol or Sevoflurane in Patients with Brain Tumors

Abstract

During propofol/fentanyl anesthesia, a large percentage of patients have jugular bulb oxygen saturation (Sjo₂) <50%. The incidence is less with isoflurane/N₂O. We evaluated the effect of N₂O on Sjo₂ during remifentanil-based anesthesia with concurrent propofol or sevoflurane in 20 adults undergoing brain tumor surgery. Anesthesia was randomized: Group 1 (n = 10), target-controlled infusion propofol; and Group 2 (n = 10), thiopental 2–3 mg/kg followed by sevoflurane 0.9% end-tidal. Jugular bulb and arterial blood samples for gas analysis were withdrawn during the administration of oxygen 33% with nitrogen 67% and then with N₂O 67%. All samples were drawn before surgery and 20 min after the addition of the study gas and with an ETco₂ 26–28 mm Hg and mean arterial pressure >90 mm Hg. Both groups had similar demographic and physiologic data. In the Propofol group, Sjo₂ was 50% ± 10% with nitrogen and 52% ± 9% with N₂O (not significant); in the Sevoflurane group, however, N₂O 67% increased Sjo₂ from 56% ± 13% to 66% ± 12% (P < 0.01). This indicates that N₂O does not reduce the incidence of low Sjo₂ values during propofol anesthesia.

Jansen et al. ⁽¹⁾ found a frequent incidence of jugular bulb oxygen saturation (Sjo₂) values compatible with global cerebral hypoperfusion in patients with brain tumors receiving propofol/fentanyl anesthesia. In contrast, all patients receiving isoflurane/nitrous oxide (N₂O) under normocapnia had normal Sjo₂. This difference can be secondary to the marked cerebral vasoconstricting effect of propofol and the fact that the combination of N₂O and isoflurane maintains or increases cerebral blood flow (CBF) and reduces cerebral metabolic rate (CMR) ⁽¹⁾.

Although N₂O is a potent cerebral vasodilator, its addition to propofol anesthesia in humans has been reported to not change middle cerebral artery red blood cell flow velocity (V_mca) ⁽²⁾. In contrast, Matta and Lam ⁽³⁾ observed an increase in V_mca, with unchanged arterial to jugular bulb venous oxygen content differences, when N₂O was added to propofol-induced electroencephalographic (EEG) silence. However, the correlation between V_mca and CBF in patients with intracranial pathology may be weak ⁽⁴⁾. In addition, Jansen et al. ⁽¹⁾ found similar absolute and relative changes in V_mca in patients given propofol/fentanyl and isoflurane/N₂O, despite significant differences in Sjo₂. This suggests that in neurosurgical patients the use of V_mca can be misleading, and that measurements of Sjo₂ might be more appropriate for monitoring cerebral ischemia. In addition, much slower infusion rates of propofol than those in the study by Matta and Lam ⁽³⁾ are typically used and, in this context, with conceivably less intense vasoconstricting activity. Thus it is possible that N₂O might increase Sjo₂ values. Finally, the effect of N₂O on Sjo₂ during inhaled anesthesia in neurosurgical patients has not been reported. The aim of this study was therefore to determine the effect of N₂O on the Sjo₂ when added to remifentanil-based anesthesia with either propofol or sevoflurane in patients with brain tumors.

Methods

After obtaining institutional ethics committee approval and written informed consent, 20 unpremedicated adult patients, ASA physical status I, scheduled for supratentorial tumor surgery, were studied prospectively. None of the patients had clinical signs of increased intracranial pressure or any known adverse effects to the study drugs. In the operating room, after routine monitoring and with patients breathing oxygen 100%, remifentanil was started at 0.3 μg · kg⁻¹ · min⁻¹; 5 min later this was increased to 0.5 μg · kg⁻¹ · min⁻¹. According to randomization, patients were allocated to Group 1 (n = 10) (target-controlled infusion propofol starting with a calculated plasma concentration of 1 μg/mL followed by 0.5 μg/mL increments every 30 s until loss of consciousness) or Group 2 (n = 10) (thiopental 2–3 mg/kg followed by sevoflurane with an end-tidal [ET] concentration of 0.9%–1.0%). Tracheal intubation was facilitated with rocuronium 0.6 mg/kg, and the lungs were mechanically ventilated to achieve an ETco₂ of 26–28 mm Hg by using an oxygen/air mixture (4 L/min fresh flow) to maintain the fraction of inspired oxygen at 0.33. During the study, anesthesia was maintained with IV remifentanil ≤0.5 μg · kg⁻¹ · min⁻¹ and target-controlled infusion propofol, defined as the concentration causing loss of consciousness, or sevoflurane ET 0.90%. The radial artery was cannulated for pressure monitoring and blood sampling. An IV phenylephrine infusion was started if necessary to maintain mean arterial pressure (MAP) >90 mm Hg. A thermocouple was placed in the nasopharynx to monitor body temperature. A catheter was inserted retrogradely into the jugular internal vein ipsilateral to the side of the tumor, and the correct placement of its tip was confirmed by radiologic inspection. After a 30-min period of stabilization, blood samples were withdrawn for hemoglobin and gas analysis (Control). Then, patients in both groups were switched to oxygen/N₂O 33%:67%, and after at least 20 min, a second set of blood samples for gas analysis was drawn. In all cases, measurements were made before surgery and mannitol administration, and jugular venous blood was withdrawn at a rate ≤2 mL/min.

The arterial (Cao₂) to jugular bulb venous oxygen content (Cjo₂) differences (AJDo₂) were calculated with the equation:MATH where Hb is hemoglobin (mg%), Sao₂ is arterial oxygen saturation, and Pjo₂ is the jugular bulb venous oxygen partial pressure. Global hypoperfusion was defined as Sjo₂ <50%, and ischemia was defined as Sjo₂ <40% and AJDo₂ >9 mL/dL.

Data were analyzed with repeated-measures analysis of variance, and the post hoc analysis was performed with paired and unpaired Student’s t-tests and Bonferroni’s correction. Fisher’s exact test was used for nonparametric data. All analyses were performed with StatView^® SE + Graphics, version 1.04 (Abacus Concepts, Inc. Berkeley, CA). A P value <0.05 was considered significant. Values are mean ± sd unless otherwise stated.

Results

There were no significant differences in demographics or physiologic data between groups (Table 1). All patients required phenylephrine infusion to maintain MAP >90 mm Hg. During control measurements, Pjo₂, Sjo₂, and AJDo₂ were similar in both groups, however, during the administration of N₂O 60%, Pjo₂ and Sjo₂ increased and AJDo₂ decreased only in the Sevoflurane group (Table 2).

Table 1: Demographic Data and Hemoglobin Concentration

Table 2: Physiologic Variables During Anesthesia

The incidence of Sjo₂ <50% during control mea-surements was 60% in the Propofol group and 20% in the Sevoflurane group (P = 0.07), and it remained unchanged with N₂O (Fig. 1). During control mea-surements, three patients (one in the Propofol group and two in the Sevoflurane group [not significant]) presented Sjo₂ <40% and AJDo₂ >9 mL/dL (Fig. 1). No patient presented a new major neurologic deficit in the early postoperative period.

Figure 1: Jugular bulb venous oxygen saturation (Sjo₂) and arterial to jugular bulb venous oxygen content differences (AJDo₂) in both groups during the administration of oxygen 33% in nitrogen (N₂) 67% (Control) and N₂O 67%. N₂O increased Sjo₂ and reduced AJDo₂ only when added to sevoflurane. • = patients who presented values compatible with cerebral ischemia (Sjo₂ <40% and AJDo₂ >9 mL/dL).

Discussion

The main finding of this study is that, in patients with brain tumors, N₂O 66% increased Sjo₂ values when added to sevoflurane/remifentanil, but not to propofol/remifentanil, anesthesia. Low Sjo₂ values during propofol have been demonstrated in both neurosurgical ^(1,5) and nonneurosurgical patients ^(6,7). These can be secondary to a larger decrease in CBF relative to the reduction of the cerebral metabolic rate of oxygen (CMRo₂), particularly during hyperventilation ^(6,8,9). Regarding sevoflurane, increasing ET concentrations from 1.0% to 3.0% resulted in no change in V_mca or Sjo₂ in normocapnic neurosurgical patients, and none of the patients studied had Sjo₂ <50%⁽¹⁰⁾. Comparisons with the awake state in nonneurosurgical patients have found both no change in V_mca with 1.0 and 1.5 minimum alveolar anesthetic concentration (MAC) sevoflurane under normocapnia ⁽¹¹⁾ and a reduction of V_mca by 20% and 37% with 1.2 MAC during normocapnia and hypocapnia, respectively ⁽¹²⁾. In contrast to propofol, there is also evidence suggesting that, at least during normocapnia, sevoflurane can produce more reduction of CMRo₂ than CBF in humans ^(13,14). Thus, the trend for an increased incidence of low Sjo₂ values in patients receiving propofol compared with sevoflurane is in agreement with these studies.

Even though N₂O is considered a potent cerebral vasodilator, its effect on cerebral hemodynamics is dependent on the basal conditions of the subject. In volunteers under normocarbia, N₂O increased CBF ^(15–20). However, during hypocapnia, the administration of N₂O resulted in no change ⁽¹⁸⁾, return of a reduced CBF to basal values ⁽²¹⁾, and even an increase in CBF compared with control values under normocapnia ⁽¹⁷⁾. In patients receiving anesthesia with volatile anesthetics, there are also diverse results. The replacement of isoflurane ET 1.7% in air/oxygen by isoflurane ET 0.85% in N₂O/oxygen (65%:35%) resulted in a 43% increase in CBF at a Paco₂ of 34 mm Hg. During hypocapnia (Paco₂ of 27 mm Hg), four of five patients showed more than a 26% increase in CBF, but this did not reach statistical significance ⁽²²⁾. Lam et al. ⁽²³⁾ found in normoventilated patients that N₂O 0.6 MAC added to isoflurane 0.5 MAC did not change CBF, although a decrease in arteriovenous oxygen content difference (AVDo₂) was observed, suggesting a reduction of CMR. Under the same conditions, but during isoflurane 1.1 MAC, the administration of N₂O produced a 25% increase in CBF and no change in AVDo₂⁽²³⁾. In a more recent study, the addition of 66% N₂O to isoflurane ET 0.8% increased CBF at Paco₂ values of 39 mm Hg, but not 29 mm Hg; however, a slowing of EEG activity was observed at both levels of Paco₂, although this was more marked during normocapnia ⁽²⁴⁾. In another study, the reduction in CBF caused by 1.2 MAC sevoflurane was reversed by the addition of 60% N₂O regardless of Paco₂⁽¹²⁾. However, Bedforth et al. ⁽¹¹⁾ found an increase in V_mca when N₂O was added to 1.0 MAC, but not to 1.5 MAC, sevoflurane in normocapnic patients. Thus, the increase in Sjo₂ when N₂O was added to small-concentration sevoflurane in our patients may have been secondary to increases in CBF, a reduction in CMR, or both.

The administration of 50, 100, and 200 μg · kg⁻¹ · min⁻¹ propofol resulted in a reduction of CBF at the two faster infusion rates but resulted in no change in CMRo₂ compared with control measurements under N₂O and phencyclidine in the baboon ⁽⁹⁾. The addition of 70% N₂O produced no further modifications in CBF or CMRo₂. In humans, 150 μg · kg⁻¹ · min⁻¹ propofol reduced V_mca compared with the awake state at Paco₂ of 30, 40, and 50 mm Hg, and no change was observed with the addition of 70% N₂O ⁽²⁾. Finally, in normoventilated nonneurologic patients with EEG silence induced by 250–300 μg · kg⁻¹ · min⁻¹ propofol, 70% N₂O increased V_mca by 21% and CMRo₂ by 14%, thus leading to no change in AVDo₂⁽³⁾. These and our results suggest that N₂O is not able to counteract the vasoconstriction produced by propofol and is not useful to prevent low Sjo₂ values during this type of anesthesia.

Compared with the awake state, CO₂ reactivity of the cerebral vessels is well maintained during 1 to 1.2 MAC sevoflurane with and without N₂O ^(12,14) and is slightly decreased during propofol anesthesia with and without N₂O ⁽²⁾. Thus, Paco₂ plays a key role in the development of low Sjo₂ values during anesthesia. Under isoflurane and Pao₂ of 100 mm Hg, neurosurgical patients presenting Sjo₂ <50% increased from 8% to 33% when Paco₂ was reduced from 30 to 25 mm Hg ⁽²⁵⁾, and a study in cardiac patients with 1 MAC sevoflurane found mean Sjo₂ of 47% and 67% at Paco₂ of 29 and 41 mm Hg, respectively ⁽¹⁴⁾. In this context, our results agree with previous studies. During propofol administration Jansen et al. ⁽¹⁾ found an incidence of Sjo₂ <50% of 50% and 80% at Paco₂ of 32 and 21 mm Hg, respectively. We found 60% at a Paco₂ of 29 mm Hg. Jansen et al. ⁽¹⁾ also observed that during isoflurane/N₂O, the incidence of Sjo₂ <50% was 0% at a Paco₂ of 35 mm Hg and 50% at a Paco₂ of 23 mm Hg. In our patients, 20% had Sjo₂ <50% during sevoflurane/N₂O at a Paco₂ of 29 mm Hg.

Finally, jugular venous oxygen is an indirect assessment of global cerebral oxygen use, and Sjo₂ <50% is considered indicative of cerebral hypoperfusion ⁽²⁶⁾. Low oxygen saturation values occur when demand exceeds supply, and this can be secondary to absolute or relative increased global or regional cerebral oxygen consumption, reduced CBF, or both. Thus therapy should be considered with Sjo₂ <50%, including increases in MAP ⁽⁵⁾, inspired oxygen concentration ⁽²⁵⁾, and Paco₂⁽²⁷⁾. However, the clinical importance of intraoperative jugular bulb desaturation remains to be proven ⁽²⁶⁾.

In conclusion, in patients with brain tumors under hypocapnia, and in contrast to what occurs during sevoflurane administration, the addition of N₂O to propofol anesthesia does not increase Sjo₂.