Low doses of esmolol and phenylephrine act as diuretics during intravenous anesthesia

During general anesthesia and surgery, renal clearance of crystalloid fluid is only 15% to 20% of that found in conscious volunteers [1‐3]. If not carefully balanced, fluid therapy entails a risk of inducing edema. Slow elimination might be counteracted by manipulation of the adrenergic balance. In awake sheep, β₁-receptor stimulation by isoprenaline caused fluid retention and excessive plasma volume expansion that closely resembles the kinetic situation during anesthesia and surgery. In contrast, α₁-receptor stimulation by phenylephrine increased urinary excretion [4, 5].

The aim of the present study was to examine to what degree the slow turnover of lactated Ringer's solution during anesthesia and surgery can be rectified by infusing esmolol (a β₁-receptor blocker) or phenylephrine in patients undergoing laparoscopic gynecological surgery during intravenous anesthesia. Based on the previous animal studies [4, 5], our hypothesis was that urinary excretion would increase in response to esmolol and phenylephrine. Kinetic analysis was also performed to elucidate whether the infusions cause an aberrant distribution of fluid.

Safety reasons stipulated that the amounts of drug provided be low. The rate of infusion of phenylephrine represented only 1% of that used for hemodynamic support. Esmolol was given in the starting dose recommended for the management of supraventricular tachyarrhythmias.

Shifting the catecholamine balance by small amounts of drug promoted urinary excretion. In the present study, esmolol doubled and phenylephrine almost tripled the excretion of infused lactated Ringer's during laparoscopic surgery. Despite the diuretic effect, the modification of the adrenergic stimulus pattern was not strong enough to clearly affect MAP or heart rate.

The average ratio of excreted/infused fluid after 3 hours in the control group (9%) was similar to that found for acetated Ringer's during laparoscopic cholecystectomy [2] and thyroid surgery [3]. However, even with the two treatment drugs, urinary excretion was still far below the 50% to 70% of the infused volume seen within 3 hours in unstressed volunteers [6] and patients awaiting laparoscopic surgery [7]. Hence, the administered esmolol and phenylephrine were not sufficient to reverse the strong antidiuretic effect of general anesthesia and surgery. On the other hand, the present results open up for the use of these drugs when both adrenergic and diuretic effects are desired. How long the difference in urinary excretion during surgery prevails is unknown. The rate is likely to increase slightly when anesthesia is terminated [2], but much of the fluid retained during surgery remains in the body for several days [8]. In contrast, infusions of crystalloid salt [7] and glucose [9] solution initiated several hours later are excreted effectively.

Why the diuretic response to plasma volume expansion is blunted during anesthesia and surgery is poorly understood but probably can be attributed to vasodilatation, reduced arterial pressure, and activation of the renin-aldosterone hormonal axis [1]. Beta-receptor activity may also play a part. The renal clearance of crystalloid fluid is slightly higher during open laparotomy [10] than during laparoscopy [2]; therefore, body position and pneumoperitoneum might also depress the renal excretion of fluid.

The physiological effects of intravenous anesthesia also promote a pronounced plasma volume expansion in response to crystalloid fluid. When the infusions ended, 60% to 70% of the infused fluid remained in the functional plasma volume, v_c. Similarly high percentages have been reported during isoflurane anesthesia [11] and during general anesthesia and surgery [2, 3, 10]. Pronounced plasma volume expansion during infusion implies that V_c is low, and this is typical of anesthesia-induced vasodilatation [1]. Here, the small V_c can also be explained by the relatively low body weight (50 to 55 kg) of the Chinese women studied. The study drugs might have altered V_c, although the average volume in the esmolol and phenylephrine groups differed very little from that of the controls.

A key finding of the kinetic analysis is that both study drugs slowed down the distribution of fluid from v_c to v_t and this probably reflects minimally decreased filtration due to vasoconstriction. This counteracted any hypovolemic effect of the increased diuresis during the first half of the experiments. The fluid volumes residing in v_c became reduced at the end of the study, but, at that time, differences were hardly worth noting. The fluid volumes in v_t did not differ significantly at 180 minutes (Figure 5).

Variable results for the diuretic effect of esmolol in previous work suggest that the present study may be relevant only to anesthetized subjects, possibly because the renin-aldosterone axis is then stimulated. Complete β₁-receptor blockade in conscious humans lowers the resting plasma levels of renin, angiotensin, and aldosterone but without affecting the diuretic response to volume loading with saline [12]. In awake sheep, esmolol reduced the diuretic response to infused fluid [13]. Moreover, more fluid tended to accumulate in the extravascular space [13] and this was not encountered during intravenous anesthesia in humans (Figure 5).

Phenylephrine increases the urinary excretion by pressure diuresis if the increase in MAP is profound, but also by increasing the release of atrial natriuretic peptides [4]. The small doses of drugs used in the present study make the role of these mechanisms speculative. These doses are, in fact, also a limitation since we cannot outline the diuretic effects of larger amounts. In sheep, larger doses of phenylephrine markedly lower the plasma volume [4, 5] but this was not an issue in the present study (Figures 4 and 5).

Another limitation was that the operations were performed on ASA I patients only. Therefore, the effects of the study drugs on patients with cardiovascular disease are unclear. Operations were also performed in a teaching hospital and this explains why more than 1 hour had passed before the surgery started. The restoration of baseline MAP between 70 and 90 minutes in all groups can be understood on the basis of the late start of the surgery (Figure 2, middle). Hence, the entire infusion and the 30-minute post-infusion period of distribution usually took place before surgery began. However, plasma volume expansion did not change abruptly when surgery started; this is not the case during emergence from anesthesia for laparoscopy [2, 14].

The main conclusion still appears to be valid when the urinary excretion is calculated for periods of apparently different MAPs and for periods of surgery and non-surgery (Tables 2 and 4). The greatest difference in urinary excretion occurred early during the procedures (that is, during periods of non-surgery, when the plasma dilution was most pronounced). The excreted volumes were smaller when surgery eventually started (and MAP was higher). Some statistical differences in urinary excretion were lost during the second half of the study. However, the average values for the groups still showed a continued trend from the first half of the experiments, namely that the treatment drugs were associated with a larger urinary excretion.

The novel kinetic analysis used here has the advantage of being able to estimate all parameters without having to discriminate between two models [1]. Drobin's model was first fitted to the data [15] but did not yield reasonable estimates for all curves. A drawback of the present approach is that the urinary excretion needs to be measured. Model stability is also increased by the fact that the size of V_t is not estimated, although it can be inferred in retrospect. The output is given in the form of V_c and three rate constants. The latter the three rate constants are implied here should be multiplied by V_c to be converted into clearances, which is used in virtually all previous publications of volume kinetics. Yes, it should be "are". I originally meant clearance as a concept, but I guess we should aim at them being three different types of clearance.

Low doses of esmolol doubled and phenylephrine almost tripled urinary excretion. These drugs may potentially be used as diuretics when renal fluid clearance is reduced by anesthesia and surgery-associated stress. Further work is needed to elucidate how the diuretic effects of these drugs are best employed. Phenylephrine might be an alternative to a conventional diuretic such as furosemide if the hemodynamics is unstable. Esmolol could be used as a mild diuretic in patients with supraventricular arrhythmias.