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Anesthesiology:
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“The Proper Study of Mankind Is Man”*—Rather, Men and Women Undergoing Anesthesia and Surgery

Prough, Donald S. M.D.

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STARTING in 1997, Hahn et al.1–4 introduced and developed the concept of volume kinetics, which describes the peak effects and clearance of intravenously infused fluids in terms similar to those used in pharmacokinetics to describe the peak effects and clearance of drugs. Stanski,5 in an editorial accompanying the landmark article by Svensen and Hahn in Anesthesiology in 1997,1 commented that the volume kinetic approach could “allow for more rational design of intravenous fluid paradigms.” Toward that end, Hahn et al. have examined several key questions in volunteers6–8 and in experimental animals.9–12 One of the least expected observations, obtained in sheep, was that isoflurane anesthesia seemed to be associated with extravascular accumulation of infused crystalloid.9 However, in this issue of Anesthesiology, Ewaldsson and Hahn13 convincingly demonstrate that, in humans, neither isoflurane nor propofol anesthesia is associated with extravascular fluid accumulation. The authors infer from their data that volume kinetics are powerfully influenced by hypotension,13 an inference that merits examination in the context of previous volume kinetic studies.
In pharmacokinetics, an exogenous substance is introduced, blood or other fluids are repeatedly sampled, and the resulting temporal pattern is analyzed to determine important kinetic variables. In contrast, volume kinetics examines the clearance of endogenous substances, e.g., water, that already are present in considerable quantities. For such studies, an endogenous tracer is necessary, the best being the blood concentration of hemoglobin, which is an obligatory intravascular tracer. To confidently calculate volume kinetic variables, the blood concentration of hemoglobin should be repeatedly measured before, during, and after fluid infusion in a relative steady state. High-probability solutions to the kinetic equations necessitate that changes in potentially confounding physiologic and pharmacologic influences be minimized for a sufficient time interval to construct clearance curves. In practice, time intervals of 180 min after the beginning of an intravenous infusion have provided sufficient data for reliable kinetic analyses.
Such time intervals of relative stability can be achieved easily in certain types of volunteer and animal studies. For example, in volunteers, isotonic crystalloid solutions were rapidly cleared,1 colloid solutions were less rapidly cleared,1 and crystalloid solutions produced higher peak volume expansion and more delayed clearance in hypovolemic than normovolemic volunteers.6 During intervals of relative stability in preeclamptic parturients, crystalloid solutions were more rapidly cleared than in normal volunteers.14 In experimental animals, isoflurane anesthesia was associated with similar clearance of infused crystalloids from blood but markedly delayed urinary excretion, implying greater extravascular retention.9,15 As in volunteers, hemorrhage in sheep both increased peak expansion and delayed clearance from blood.12 Pseudomonas bacteremia, which in sheep mimics many characteristics of clinical sepsis, unexpectedly did not influence volume kinetics.16 In sheep, continuous infusion of α-adrenergic agonists dramatically accelerated, whereas β agonists delayed, clearance of infused crystalloids.17
However, the clinical circumstances of anesthesia and surgery usually preclude 180 min of steady state conditions, the influences of surgical stress and surgically induced fluid shifts are difficult to separate from the influence of anesthesia, and blood loss confounds kinetic analyses based on measurements of the blood concentration of hemoglobin. Nevertheless, volume kinetic studies have been performed in patients undergoing surgery. During laparoscopic cholecystectomy in women undergoing sevoflurane–narcotic anesthesia, induction of anesthesia, before fluid infusion, was associated with 4.2% plasma dilution (equivalent to intravascular volume expansion); subsequent fluid infusion was associated with calculated kinetic variables that were similar to those acquired in female volunteers, despite marked inhibition by anesthesia of the infusion-associated diuresis seen in volunteers.18 In contrast, in men undergoing prostatectomy during enflurane anesthesia, crystalloid fluids seemed to produce greater volume expansion than in unanesthetized volunteers.19 In a heterogeneous group of patients undergoing elective surgery of variable magnitude during subarachnoid block or sevoflurane–narcotic general anesthesia, volume expansion was greater in patients undergoing general anesthesia, but urinary elimination was similarly reduced in both groups.20 Men undergoing short urologic procedures during epidural anesthesia retained a relatively high proportion of infused volume intravascularly.21
Together, these studies demonstrate the difficulty of separating the effects of volume kinetics during anesthesia and surgery. The magnitude of surgery and the hemodynamic responses to anesthetic and surgical manipulations varied substantially, with the most striking effects being differences in blood pressure. In the women undergoing cholecystectomy, induction of anesthesia was associated with hypotension so that blood pressure was substantially lower than baseline when fluid infusion began as surgery started; data collection for volume kinetic analysis continued for at least 2 h after completion of surgery, during which time blood pressure returned toward preanesthetic values.18 In the comparison of general and subarachnoid anesthesia, a 60-min, 20-ml/kg fluid bolus was initiated 20 min before anesthetic induction.20 Data were collected only until the end of the infusion, during which time blood pressure was 30–40 mmHg below the preinduction baseline in both groups, with the greater reduction occurring in the group receiving subarachnoid blocks. In men undergoing urologic surgery during epidural anesthesia, greater reductions in blood pressure were associated with greater intravascular retention of fluid.21
The study published in this issue of Anesthesiology was well designed to minimize the influence of surgical manipulation and partially isolate the influence of anesthesia while providing sufficient time to collect samples for kinetic analysis.13 Thyroid surgery, which is associated with little soft tissue manipulation, lasted a mean of 143 min—sufficient time to complete most kinetic analyses. Anesthetic management was randomized to permit comparison of the effects of isoflurane and propofol. Although no control data were collected in unanesthetized patients, published data from unanesthetized subjects were available for comparison. The greater intravascular retention of fluid, in comparison to unanesthetized subjects in previous studies,1 was associated with hypotension during both propofol and isoflurane anesthesia. Fractional plasma dilution was greater than in previously studied, unanesthetized volunteers, in association with reductions of 30–40 mmHg in both anesthetized groups.
These data should encourage advocates of crystalloid fluid therapy. Intravascular volume expansion produced by crystalloid fluids was increased during anesthesia in humans, and excess interstitial accumulation of fluid did not occur. Why do these data seem to conflict with data in sheep? One possibility is that because the sheep in the previously cited studies9,15 did not have development of hypotension, the effects of anesthesia per se were evident. Perhaps anesthesia is associated with intravascular fluid retention if hypotension is prominent and with extravascular fluid retention if blood pressure is maintained at a higher level. In the surgical patients in the current study, the reduction in blood pressure seems to have provided the dominant influence. Further studies are necessary to determine the influence on volume kinetics of “typical” clinical anesthetic management, in which blood pressure is maintained closer to preoperative baseline than in the current study.
Donald S. Prough, M.D.
University of Texas Medical Branch, Galveston, Texas. dsprough@utmb.edu
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References

1. Svensen C, Hahn RG: Volume kinetics of Ringer solution, dextran 70, and hypertonic saline in male volunteers. Anesthesiology 1997; 87:204–12

2. Stahle L, Nilsson A, Hahn RG: Modelling the volume of expandable body fluid spaces during i.v. fluid therapy. Br J Anaesth 1997; 78:138–43

3. Hahn RG, Drobin D, Stahle L: Volume kinetics of Ringer’s solution in female volunteers. Br J Anaesth 1997; 78:144–8

4. Hahn RG, Drobin D: Urinary excretion as an input variable in volume kinetic analysis of Ringer’s solution. Br J Anaesth 1998; 80:183–8

5. Stanski DR: The pharmacokinetics of intravenous fluids. Anesthesiology 1997; 87:200–1

6. Drobin D, Hahn RG: Volume kinetics of Ringer’s solution in hypovolemic volunteers. Anesthesiology 1999; 90:81–91

7. Drobin D, Hahn RG: Kinetics of isotonic and hypertonic plasma volume expanders. Anesthesiology 2002; 96:1371–80

8. Svensen C, Drobin D, Olsson J, Hahn RG: Stability of the interstitial matrix after crystalloid fluid loading studied by volume kinetic analysis. Br J Anaesth 1999; 82:496–502

9. Brauer KI, Svensen C, Hahn RG, Traber LD, Prough DS: Volume kinetic analysis of the distribution of 0.9% saline in conscious versus isoflurane-anesthetized sheep. Anesthesiology 2002; 96:442–9

10. Brauer LP, Svensén C, Hahn RG, Kilicturgay S, Kramer GC, Prough DS: Influence of rate and volume of infusion on the kinetics of 0.9% saline and 7.5% saline/6.0% dextran 70 in sheep. Anesth Analg 2002; 95:1547–56

11. Svensen CH, Brauer KP, Hahn RG, Uchida T, Traber LD, Traber DL, Prough DS: Elimination rate constant describing clearance of infused fluid from plasma is independent of large infusion volumes of 0.9% saline in sheep. Anesthesiology 2004; 101:666–74

12. Norberg A, Brauer KI, Prough DS, Gabrielsson J, Hahn RG, Uchida T, Traber DL, Svensen CH: Volume turnover kinetics of fluid shifts after hemorrhage, fluid infusion, and the combination of hemorrhage and fluid infusion in sheep. Anesthesiology 2005; 102:985–94

13. Ewaldsson CA, Hahn RG: Kinetics and extravascular retention of acetated Ringer’s solution during isoflurane and propofol anesthesia for thyroid surgery. Anesthesiology 2005; 103:460–9

14. Drobin D, Hahn RG: Distribution and elimination of crystalloid fluid in pre-eclampsia. Clin Sci (Lond) 2004; 106:307–13

15. Connolly CM, Kramer GC, Hahn RG, Chaisson NF, Svensen CH, Kirschner RA, Hastings DA, Chinkes DL, Prough DS: Isoflurane but not mechanical ventilation promotes extravascular fluid accumulation during crystalloid volume loading. Anesthesiology 2003; 98:670–81

16. Svensen CH, Clifton B, Brauer KI, Olsson J, Uchida T, Traber LD, Traber DL, Prough DS: Sepsis produced by Pseudomonas bacteremia does not alter volume expansion after 0.9% saline infusion in sheep. Anesth Analg 2005; 101:835–42

17. Vane LA, Prough DS, Kinsky MA, Williams CA, Grady JJ, Kramer GC: Effects of different catecholamines on the dynamics of volume expansion of crystalloid infusion. Anesthesiology 2004; 101:1136–44

18. Olsson J, Svensen CH, Hahn RG: The volume kinetics of acetated Ringer’s solution during laparoscopic cholecystectomy. Anesth Analg 2004; 99:1854–60

19. Hahn RG: Volume effect on Ringer’s solution in the blood during general anaesthesia. Eur J Anaesthesiol 1998; 15:427–32

20. Ewaldsson CA, Hahn RG: Volume kinetics of Ringer’s solution during induction of spinal and general anaesthesia. Br J Anaesth 2001; 87:406–14

21. Drobin D, Hahn RG: Time course of increased haemodilution in hypotension induced by extradural anaesthesia. Br J Anaesth 1996; 77:223–6

* Alexander Pope: Essay on Man. Epistle ii. Lines 1, 2. 1733. Cited Here...

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