CFS Electrolytes and Anesthetic Requirement
404
Anesth Analg 57:404-410, 1978
6rain Sodium, Potassium, and Osmolality: Effects on Anesthetic Requirement YASUMASA TANIFUJI, M.D.* EDMOND I . EGER, 11, M.D.t San Francisco, California:
N-e determined the effects of hyperkalemia, h y pernatremia, hyperosmolality and hypo-osmolality on halothane requirement (MAC) in dogs. Hyperkalemia did not change cerebrospinal fluid potassium or MAC. HyDernatremia Dro~portionately increased cerebrospinal fluid sodiunl and osmolality. MAC c-ncomitantly increased 43%. Serum hyperosmolality b> administration of 12 and 25% dextrose increased cerebrospinal fluid osmolality without
D
or therapeutic intervention may alter body electrolytes and osmolality. Patients with impaired kidney function, dehydration, hyperalimentation, or chronic steroid hormone administration can show considerable changes in serum electrolytes and osmolality. We may impose such changes by I V infusion of salt-free solutions or by irrigation of bladder or stomach with saltfree solutions. Although we prefer to correct electrolyte and osmotic imbalances prior to anesthesia, this is not always possible or desirable. ISEASE
The excitability of nervous tissue depends in part on the intracellular and extracellular distribution of sodium and potassium.l An excess of extracellular potassium causes membrane depolarization. An excess of extracellular sodium causes hyperpolarization. Although hyperpolarization decreases the excitability of the neuron, it results in a
appreciably altering cerebrospinal fluid sodium or MAC. Infusion of 5 % dextrose produced hypo-osmolaiity of blood and cerebrospinal fluid. Cerebrospinal fluid sodium was diluted and MAC was reduced bv- 24%. ,Key FVOrds-POTENCY, anesthetic, MAC. -ANESTHETICS, volatile, halothane. IONS, sodium- IONS, Potassium. CEREBROSPINAL FLrlD* osmo'ality-
larger nerve-action potential and probably a greater release of neurotransmitter a t the synapse.? A reduction in the nerve-action potential by an increase in extracellular potassium might do the opposite. The relationship between the size of the nerve-action potential and the release of transmitter is such that a 15-mv increase in depolarization produces a tenfold increase in neurotransmitter release.? On the other hand, hyperpolarization would decrease the excitability of the postsynaptic membrane adjacent to the subsynaptic membrane and therefore should lead to a block of synaptic transmission. The foregoing observations suggest that changes in the electrolyte concentrations bathing nerves might influence anesthetic requirements. Indeed, an imbalance of electrolytes has been suggested as causally related to the development of anesthesia.3
'Fellow in Research Professor of Anesthesia XDepartment of Anesthesia, University of California, San Francisco, California 94143 Suppoi ted by USPHS GM 15571. the Foundation for In Service Training and Welfare of the Private School Personnel in Japan, and by a grant from the Anesthesia Research Foundation Address reprint requests to Dr. Eger. Accepted for publication: Marrh 14, 1978 7
Anesth Analg
Tanifuji and Eger
57:404-410. 1978
Ionic changes (specifically calcium) may affect the phase changes in phosphatidylserine bilayers induced by cyclopropane.4 Such an influence may be of importance if alteration of nerve-membrane fluidity is the means by which anesthetics exert their effect.*,G Anesthetic requirement may be affected by changes in magnesium,? calcium (Johnson and Crout, Abstracts of Scientific Papers, American Society of Anesthesiologists Meeting, New York, 1970, p l ) , lithium,5 or bromide.9 No reports have indicated the effect of altering the major normal serum ions or serum osmolarity on the dose requirement of general anesthetics. The following report supplies such data. Our results suggest that alterations in brain extracellular sodium may directly affect anesthetic requirement (MAC*).
METHODS Thirty-three unpremedicated dogs of various ages, breeds, sexes) and weight (mean 23 2 1 kg) were divided into 6 groups. Anesthesia was induced and maintained with halothane in 02.A cuffed endotracheal tube was introduced without the use of muscle relaxants, and breathing was controlled with a volume-limited respirator to achieve an end-tidal C02 (infrared analysis) of 4 to 5%. Intermittent end-tidal gas samples were obtained from the end of the endotracheal tube via a nylon catheter. Halothane concentration was measured with a Beckman LB-1 infrared analyzer. Esophageal temperature was measured and maintained between 36.5 and 38.5 C by external heating or cooling. MAC was determined as described previously, using tail clamp as the stimu1us.lO All measurements were made after 15 minutes at a constant end-tidal halothane concentration. Arterial blood for blood-gas analysis was drawn from a catheter inserted into the femoral artery. Using a 19-gauge needle, we punctured the cisterna magna a t the times indicated below to measure cerebrospinal fluid pressure and to obtain fluid samples for acid-base, osmotic and electrolyte determinations. Pco2 and pH were measured with standard electrodes. Osmolality was determined by the freezingpoint technic. Sodium and potassium con*MAC is the minimum alveolar concentration of anesthetic required to abolish movement in response to a painful stimulus in 50% of animals. It is an anesthetic EDEowhich ordinarily is unaffected by a variety of factors, including duration of anesthesia.10
405
centrations in blood and in cerebrospinal fluid were determined by flame photometry. Pressures in the femoral artery and the cisterna magna were transduced with Statham strain gauges and recorded with the ECG on a Grass polygraph. After induction with halothane, we determined MAC (control) and drew samples of blood and cerebrospinal fluid. In group 1 dogs (6 dogs), we then infused a solution containing 160 mEq/L of potassium chloride.We adjusted the infusion to the maximum permitted by alterations in the ECG and blood pressure. After 3 to 4 hours of infusion and again after 7 to 8 hours of infusion, we redetermined MAC and obtained blood and cisternal fluid. In a 2nd group ( 8 dogs), we examined whether changes in sodium altered halothane MAC. A control MAC was determined, and arterial blood and cerebrospinal fluid obtained for analysis. We then administered 10 mEq/kg/hr of a 510 mEq/L sodium chloride (3% NaCl) infusion to which we added 50 mEq/L of sodium bicarbonate and 10 mEq/L of potassium chloride. This solution was i n f w d for 4 hours. Between the 3rd and 4th hour, MAC was redetermined, and blood and cerebrospinal fluid samples again were obtained. After that, 1000 ml of 5% dextrose in H 2 0 were given IV along with 2000 ml of distilled H 2 0 instilled into the stomach via an orogastric catheter. After an additional 4 hours, we redetermined MAC, and blood and cerebrospinal fluid samples were drawn. Next) we examined the influence of changes in serum osmolarity achieved with nonelectrolytes on MAC and cerebrospinal fluid, electrolytes, and osmolality. In the 3rd group (3 dogs), we determined a control MAC and took arterial blood and cerebrospinal fluid samples. Then 4 g/kg/hr of mannitol were infused for 4 hours. MAC was redetermined in the 4th hour of infusion, and arterial blood and cerebrospinal fluid again were obtained for analysis. In the 4th group (6 dogs), after the determination of a control MAC and electrolytes and osmolality in serum and cerebrospinal fluid, 500 ml/hr of 25% dextrose were infused for 3 hours. MAC was redetermined in the 3rd hour, and blood and cerebrospinal fluid obtained. In the 5th group ( 5 dogs), we determined a control MAC, and took blood and cerebrospinal fluid samples. Then 1000 ml/hr of
406
Anesth Analg
CFS Electrolytes and Anesthetic Requirement
1274 dextrose were infused for 4 hours and MAC redetermined in the 4th hour. Blood and cerebrospinal fluid analyses were obtained after redetermination of MAC.
In the 6th group (5dogs), a control MAC was determined and blood and cerebrospinal fluid samples were drawn. We then administered 1000 ml/hr of 5% dextrose for 4 hours. MAC was redetermined, and blood and cerebrospinal fluid again were obtained during the 4th hour of infusion. Paired or unpaired Student's &tests were used to determine the significance of changes seen in MAC, electrolytes, and osmolality in serum and cerebrospinal fluid. A p value of less than 0.05 was accepted as significant.
RESULTS Group 1 (Potussium lnfmion1 - Serum potassium increased both a t the 4th and the 8th hour of infusion (table). cerebrospinal fluid potassium increased significantly but the increase was slight (11% at 8 hours compared to a 95% increase in serum). As might be expected, MAC did not change. Group 2 (Hypertonic Suline lnfusion 1Cerebrospinal fluid sodium increased 31 mEq/L (25%) in parallel with a 36 mEq/L increase in blood sodium. At the same time, cerebrospinal fluid potassium and osmolality increased 37 and 20%, respectively. The associated 43% increase in MAC was significant. Infusion of 5% dextrose accompanied by intragastric instillation of distilled H 2 0 eliminated all significant differences that had appeared at 3 to 4 hours. Note that n equals 5 for this group and that therefore the control values are slightly different from those listed under control in the table.
Group 6 (5% Dextrose Infusion)-MAC and serum and cerebrospinal fluid sodium and osmolality decreased significantly. In the 3rd through 6th groups a serum metabolic acidosis was present, probably secondary to dilution of serum base. This acidosis was not reflected in the cerebrospinal fluid, Cerebrospinal fluid acid-base status did not change significantly in any group. DISCUSSION Cerebrospinal fluid more closely represents brain extracellular fluid than plasma and hence we have emphasized the correlates of MAC with ionic changes in cisternal fluid. The blood-brain barrier appears to prevent alterations in some cerebrospinal fluid ions. Thus, in our experiment the ser u m potassium nearly doubled but cerebrospinal fluid potassium changed only slightly. That potassium does not easily cross the cerebrospinal fluid-brain barrier has been observed by other workers.11.1:3 As might be expected, in the absence of spinal fluid changes, MAC did not change with hyperkalemia. Cerebrospinal fluid potassium did change with other treatments. Both 12 and 25% dextrose infusions, mannitol infusion, and hypertonic saline infusion were associated with an increase in potassium. However, only the hypernatremia-associated increase in potassium altered MAC (table, fig 11.
Group 3 ( Munnitol Znfusion)-Although serum sodium decreased 10 mEq/L, cerebrospinal fluid sodium, potassium, osmolality, and MAC significantly increased, by about the same amount as in group 2. Group 4 (25% Dextrose lnfmion)--Serum sodium decreased 14 mEq/L while cerebrospinal fluid osmolality increased significantly (60 m mm, as in group 2 ) . Cerebrospinal fluid sodium rose slightly. MAC was not significantly increased. Group 5 (12% Dextrose infusion)-Serum osmolality increased and serum sodium decreased significantly but neither cerebrospinal fluid sodium nor MAC was changed. Cerebrospinal fluid osmolality increased significant 1y .
57.404-410, 1978
5% Dextrose I
2.2
3.0
3B
rnEq/L CSF K'
FIG 1. The correlation of changes in MAC with change in cerebrospinal fluid (CSF) potassium applied only to the results obtained with infusion of hypertonic saline (hypematremia) or mannitol (see table for mannitol data). Hypertonic (12 or 25%) dextrose infusions increased potassium without altering MAC while 5cj6 dextros: infusion decreased MAC without altering potassium. The bars at each point indicate the standard error for MAC and for potassium. T h e closed symbols indicate control values while the open symbols indicate the associated t.est values.
149 & 2 2.7
CSF
1 4 7 2 3 3.9 2 .2 301 2 2
154 2 1 3.0 2 .l 302 2 3
Blood
CSF
151 2 2 2 . 7 2 . l 3 0 2 2 2
CSF
4
146 ? 2 3.7 2 .3 301 & 4
&
Blood
.l 305
150 ? 2 2.6
CSJ? &
1 4 7 2 2 3 . 7 & .l 3 0 6 & 6
Blood
.l 3 0 0 2 4
147 2 2 2.7
CSF %
138 2 3 4.4 2 .2 301 2 7
Blood
&
2
1.09 2 .04
MAC
K+
14323
2 . 6 2 .l*
140 % 2* 6 . 8 2 .2*
NO+
-
-
Osm
1.07 & .05
MAC
1.04 & .06
.95 2 .07
.97 2 .04
1.13 2 .08
398 & 4
3.3 &
133 2 3% 2.6 & .l
276 % 3*
271 2 5* .79
&
.05*
358 ? 10:' .92 ? .07 .l':' 346 e 8%
119 & 3* 4.0 2 .2
155 & 2
.lo';:
1.04 2 .04
lo:*
370 2 14
.3* 359 &
106 & 1' 4.9 2 .4
166 2 3* 3.7
133 & 2'$ 3.8 2 .5
1.49 2 176 % 4* 3.7 2 .l* 379 & 6 +
123 2 3'< 4.5 2 .5
K+
8th hour
3.3 2 .3
3 . 2 2 .l
Recovery
142 2 3 2.7 2 . l *
140 & 3* 7.4 ? .5
NO+
lest
179 2 4* 4.8 2 .5* 373 2 8% 148& 2 1.00 2 .06 1.43 & .lo* .l 302 & 2 181 2 3* 3.7 + - .I;;: 361 + - 74: 161 & 2 &
143 2 2 3.7
Blood
.2 299
-
148 e 1 2.5 2 .l
CSF
&
-
148 2 1 3.8 2 .2
Osm
Blood
K+
4 t h hour
328 2 10
312 % 9
(n= 5)
-
-
0 sm
(n= 5)
~
1.02 2 .14
1.09 2 .04
MAC
;:Significantly different fmm control, 'Control" refers to values plus or minus t h e standard error obtained before infusions began, mhile "test" refers to values obtained 3 to 4 hours following the s t a r t of infusion and. in t h e case of groups 1 a n d 2. 7 t o U hours following t h e s t a r t of infusion. Electrolytes a r e mEq/I,, O s m i> mOsm/L, a i d M A C is psrcent halothane.
Group 6 5rk D / W ( n = 5)
Group 5 12% D / W ( n = 5)
Group 4 25(,4 D / W ( n = 6)
Group 3 Mannitol ( n = 3)
Group 2 Hypertonic saline (n = 8)
Group 1 H y perkalemia ( n = 6)
N.3+
Control
TABLE Summary of Results
408
Liley reported that an increase in osmotic pressure increased the frequency of s p n taneous discharges at the neuromuscular junction.13 This suggests that hyperosmolality increases nervous irritability and neurotransmitter discharge. Thus, a change in osmolality might influence anesthetic requirement. To distinguish between osmolality and sodium changes as the cause of the change in MAC, we tried to change amolality independently of sodium by infusing dextrose or mannitol. The success of this approach was determined by the ability of mannitol and dextrose to cross the bloodbrain barrier. One group of workers has suggested that an infusion of 4 g/kg/hr of mannitol for 4 hours injures the cerebrospinal fluid-brain barrier and allows mannitol to cross into the cerebrospinal fluid.14 Our results do not confirm this suggestion. Cerebrospinal fluid osmolality in group-3 dogs increased significantly, but the increase in cerebrospinal fluid sodium coupled with the associated negatively charged ions explains the osmolality change. In any event, since both sodium and osmolality increased, we could not estimate their relative effect on MAC. Although there is some limitation to the passage of dextrose into cerebrospinal fluid, the limitation is only partia1.l; We found (data not shown) that the cerebrospinal fluid dextrose equaled about 30% of the plasma concentration. Administration of either 25 or 12% dextrose (group 4 and 5) increased cerebrospinal fluid osmolality with either small (group 4 ) or no (group 5) increases in cerebrospinal sodium ( table, fig
T
/T
Hypertomc %lie
1
Anesth Analg
CFS Electrolytes and Anesthetic Requirement
I2 % Dextrose 5$Dex+,om
300
340
CSF
300
rnOsm/L
FIG 2. MAC correlated with the increase in osmolarity caused by hypertonic saline infusion or the decrease in osmolarity associated with 5 7 ~dextrose infusion. Administration of 12 or 25qc dextrose increased osmolarity without increasing MAC.
57:404.410, 197R
r MAC
1
T
1.0
I1 ~ , 8&/.,/5 % Dextrose A
I40
I60 mEq/L CSF Na’
I80
FIG 3. MAC consistently increased with an increase in cerebrospinal fluid sodium and decreased with a decrease in sodium.
2). MAC did not change remarkably in either group. Administration of 5% isotonic dextrose (group 6) reduced both cerebrospinal fluid sodium and osmolality. This dilution of cerebrospinal fluid sodium was associated with a reduction in MAC- Thus, in conflict with what might be predicted from Liley’s work, our results suggest that changes in osmolality do not exert a major effect on anesthetic requirement. Sodium does cross the cerebrospinal-brain barrier.1‘;-l9 Hypernatremia probably increased cerebrospinal fluid sodium not only by sodium crossing the blood-brain barrier, but also by dehydration secondary to administration of hyperosmotic solutions. Dehydration is reflected in the concomitant cerebrospinal fluid potassium and osmolality increase. The increased MAC in group 2 correlated well with cerebrospinal fluid sodium (table, fig 3 ) . The correlation of anesthetic requirement with changes in cerebrospinal fluid sodium also extended to the infusions of mannitol and 5% dextrose (table, fig 3 ) . Infusion of 25% dextrose produced a small (12 mEq/L) but significant increase in sodium. The associated small increase in the average MAC (0.07% halothane) was not significant. The other infusions produced changes in sodium and MAC that were too small to discern associated alterations (table). Our data suggest that changes in serum electrolytes or osmolality may be associated with changes in anesthetic requirement when they induce changes in brain sodium. Thus, many fluids that we (5% dextrose in H20, hypertonic saline, 5% dextrose in lactated Ringer’s solution) or our surgical colleagues
Anesth Analg 57:404-410, 1978
Tanifuji and Eger
(mannitol, distilled H20 for transurethral resection or gastric lavage) give may alter anesthetic requirement. I n the same way, disease states which increase or decrease cerebrospinal fluid sodium (eg, dehydration, diabetes insipidus) may alter anesthetic requirement. The relationship of MAC with sodium may be of theoretical interest. One explanation may be found in the work of Finck, Ngai, and Berkowitz.20 They suggested that anesthetics may act in part or whole by releasing enkephalin, a naturally occurring opiatelike substance found in both brain and spinal cord. Indeed they found that the administration of naloxone increased anesthetic requirement for a number of inhaled agents. The connection with sodium comes from the demonstration that sodium inhibits the binding of opiates to opiate receptors in the brain and thereby presumably interferes with the action of both endogenous and exogenous narcotics21 However, this effect of sodium is shared by and we have found (unpublished data) that lithium administration decreases MAC. Another explanation may lie in the potential effect of sodium on transmitter release. As noted earlier, it is known that an increase in extracellular sodium increases the transmembrane potential and the nerve action potential.] Diamond, Havdala, and Sabelli demonstrated that an increase in extracellular sodium antagonizes the depression of the nerve action potential produced by enflurane, halothane, or ketamine.?:]Release of neurotransmitter is directly related to the size of nerve action potential.? This suggests the possibility of a competitive effect of anesthesia and sodium at the nerve terminal. Diamond’s group also found that the threshold for depolarization was lowered by an increase in sodium.23 They demonstrated that the blockade of nervous transmission produced by halothane, enflurane, or ketamine at low sodium concentrations could be antagonized by raising the sodium concentration. Such an antagonism might apply both to the nerve terminal and to the postsynaptic membrane. The work of Shrivastav and his associates also may be pertinent to our findings. They found that trichloroethylene24or ketamine:: may decrease the peak of the nerve action potential by increasing resting sodium permeability and hence intracellular sodium. AS suggested in the introduction, this might impair transmitter release. A difficulty in
409
the interpretation of the importance of Shrivastav’s work is that the concentrations of anesthetic used were well beyond those required for anesthesia.
ACKNOWLEDGMENT Halothane ( FluothaneF) for this study was donated by Ayerst Laboratories.
REFERENCES 1. Hodgkin AL, Huxley AF: A quantitative description of membrane current and its applira!ion to conduction and excitation in nerve. J Physiol 117: 500-544, 1952
2. Katz B: The transmission of in~pulsesfrom neive to muscle and !he subcellular unit of synaptic action. Proc R SOCLond ( B ) 155:455-479, 19G2
3. Bennett PB, Hayward A J : Eledrolyte in]. balance as the merhanism for inert gas narcosis and anaesthesia. Nature 213(2) :938-939, 196i 4. Simon SA, MarDonald RC. Bennett PB: Phase changes induced by cyclopropane of phosphatidylserine bilayers in the presence and absenre of calriuni. Biochem Biophys Res Comniun 6 i :988.994, I975
5. Trudell J R , Hubbell WL, Cohen EN: The effect of two inhalation anesthetics on the order of spin-labeled phospholipid vesicles. Biochiin Biophvs Acta 291:321-327, 1973
6. Ueda I, Shieh DD. Eyring H : Anesthe!ic interaction with a model ce11 membrane: expansion. phase transi!ion. and melting of !he leci!hin monolayer. Anesthesiology 41 :217-225, 19i4 7. Mel!zer SJ. Auer J : Physiological and pharmacological studies of magnesium salts. Am J Physiol 15:38i-405, 1906
8. Mannisto PT, Saarnivaara L: Effect of lithium and rubidium on the sleeping !ime mused by various intravenous anaesthe!ics in !he mouse. Br J Anaesth 48:185-189, 1 9 i 6 9. Tinker J H , Gandolfi AJ. Van Dyke RA: Elevation of plasma bromide levels in patients following halothane anesthesia. Anes!hesiology 44: 194-196, 1976 10. Eger I31 11, Saidman LJ. Brands!ater B: Minimum alveolar anesthetir concentm!ion: a standard of anes!hetic potency. Anesthesiology 26: i56-763,1965 11. Bekaert J, Demeester G: Influence of the potassium concentration of !he blood on !he potassium level of the cerebi-ospinal fluid. E x p Med Surg 12:480-501, 1954 12, Bradbury MWB, Davson H : The transport of potassium between blood. rerebrospinal fluid and brain. J Physiol (London) 181:151-1i4, 19%
13. Liley AW: An investigation of spon!aneous artivity at the neuromusciilar junc!ion of !he rat. J Physiol 132:656-666, I956 14. Stuar! FP, Tories E. Fletcher R, et al: Eff e d s of single. repeated and massive mannit01 infusion in !he dog: structural and fundional rhanges in kidney and brain. Ann Surg 172:190-204, 19iO
410
CFS Electrolytes and Anesthetic Requirement
Anesth Analg 57:404.410, 1978
15. Fishman RA: Carrier transport of glucose hetween hlood and cerehrospinal fluid. Am J Physiol 206:836-844, 1964
21. Pert CB, Pasternak G, Snyder SH: Opiate agonists and antagonists discriminated by receptor hinding in brain. Science 182: 1359.1361, 1973
16. Schain R J : CSF and serum cation levels. Arch Neurol 11:330-333, 1964
22. Pert CB, Snyder SH: Opiate receptor hinding of agonists and antagonists affected differentially hy sodium. Mol Pharmacol 10:868-879, 1974
17. Pape LG, Katzman R: Effects of hydration on h h o d and cerebrospinal fluid osmolalities. Proc Soc Exp Biol Med 134:430-433, 1970 18. Bakay L: Studies in sodium exchange. Neurology 10:564571, 1960
23. Diamond BI, Havdala HS, Sahelli HC: Differential memhrane effects of general and local anesthetics. Anesthesiology 43:651-660, 1975
19. Davson H, Pollay M : T h e turnover of 24Na in the cerehrospinal fluid and its bearing on the blood-brain barrier. J Physiol 167:247-255, 1963
24. Shrivastav BB, Merahashi T, Kitz FLJ, e t al: Mode of action of trichloroethylene on squid axon membranes. J Pharmacol Exp Ther 199:179-188, 1976
20. Finck AD, Ngai SH, Berkowitz BA: Antagonism of general anesthesia by naloxone in the rat. Anesthesiology 46: 241-245, 1977
25. Shrivastav BB: Mechanism of ketamine hlock of nerve conduction. J Pharmacol Exp Ther 201: 162-170, 1977
MYOCARDIAL CHANGES I N MALIGNANT HYPERTHERMIA Although considerable information is available about the structural and biochemical changes in the skeletal muscles of patients with malignant hyperthermia, little is known of the cardiac changes in this disease. However, ventricular fibrillation and cardiac arrest occur frequently. In 3 patients with malignant hyperthermia, contraction bands and foci of myofiberlysis were found in the heart at necrnpsy. Ultrastructurally, areas nf myofiber overstretching adjacent to contraction bands and foci of extensive myofiberlysis were associated with disruptions of the sarcolemma. Similar ultrastructural findings were seen in the skeletal muscles of these patients and may be responsible fnr the hyperkalemia which is a constant feature of nidignant hyperthermia. The ventricular arrhythmias frequent in this disease are likely the result of direct damage to cardiac muscle rather than secondary to eIevated plasma Ievels of potassium. (Fenoglio JJ Jr, Irey N S : Myocardial changes in mslignant hyperthermia. A m J Path01 S9:51-58, 1977)
404
Anesth Analg 57:404-410, 1978
6rain Sodium, Potassium, and Osmolality: Effects on Anesthetic Requirement YASUMASA TANIFUJI, M.D.* EDMOND I . EGER, 11, M.D.t San Francisco, California:
N-e determined the effects of hyperkalemia, h y pernatremia, hyperosmolality and hypo-osmolality on halothane requirement (MAC) in dogs. Hyperkalemia did not change cerebrospinal fluid potassium or MAC. HyDernatremia Dro~portionately increased cerebrospinal fluid sodiunl and osmolality. MAC c-ncomitantly increased 43%. Serum hyperosmolality b> administration of 12 and 25% dextrose increased cerebrospinal fluid osmolality without
D
or therapeutic intervention may alter body electrolytes and osmolality. Patients with impaired kidney function, dehydration, hyperalimentation, or chronic steroid hormone administration can show considerable changes in serum electrolytes and osmolality. We may impose such changes by I V infusion of salt-free solutions or by irrigation of bladder or stomach with saltfree solutions. Although we prefer to correct electrolyte and osmotic imbalances prior to anesthesia, this is not always possible or desirable. ISEASE
The excitability of nervous tissue depends in part on the intracellular and extracellular distribution of sodium and potassium.l An excess of extracellular potassium causes membrane depolarization. An excess of extracellular sodium causes hyperpolarization. Although hyperpolarization decreases the excitability of the neuron, it results in a
appreciably altering cerebrospinal fluid sodium or MAC. Infusion of 5 % dextrose produced hypo-osmolaiity of blood and cerebrospinal fluid. Cerebrospinal fluid sodium was diluted and MAC was reduced bv- 24%. ,Key FVOrds-POTENCY, anesthetic, MAC. -ANESTHETICS, volatile, halothane. IONS, sodium- IONS, Potassium. CEREBROSPINAL FLrlD* osmo'ality-
larger nerve-action potential and probably a greater release of neurotransmitter a t the synapse.? A reduction in the nerve-action potential by an increase in extracellular potassium might do the opposite. The relationship between the size of the nerve-action potential and the release of transmitter is such that a 15-mv increase in depolarization produces a tenfold increase in neurotransmitter release.? On the other hand, hyperpolarization would decrease the excitability of the postsynaptic membrane adjacent to the subsynaptic membrane and therefore should lead to a block of synaptic transmission. The foregoing observations suggest that changes in the electrolyte concentrations bathing nerves might influence anesthetic requirements. Indeed, an imbalance of electrolytes has been suggested as causally related to the development of anesthesia.3
'Fellow in Research Professor of Anesthesia XDepartment of Anesthesia, University of California, San Francisco, California 94143 Suppoi ted by USPHS GM 15571. the Foundation for In Service Training and Welfare of the Private School Personnel in Japan, and by a grant from the Anesthesia Research Foundation Address reprint requests to Dr. Eger. Accepted for publication: Marrh 14, 1978 7
Anesth Analg
Tanifuji and Eger
57:404-410. 1978
Ionic changes (specifically calcium) may affect the phase changes in phosphatidylserine bilayers induced by cyclopropane.4 Such an influence may be of importance if alteration of nerve-membrane fluidity is the means by which anesthetics exert their effect.*,G Anesthetic requirement may be affected by changes in magnesium,? calcium (Johnson and Crout, Abstracts of Scientific Papers, American Society of Anesthesiologists Meeting, New York, 1970, p l ) , lithium,5 or bromide.9 No reports have indicated the effect of altering the major normal serum ions or serum osmolarity on the dose requirement of general anesthetics. The following report supplies such data. Our results suggest that alterations in brain extracellular sodium may directly affect anesthetic requirement (MAC*).
METHODS Thirty-three unpremedicated dogs of various ages, breeds, sexes) and weight (mean 23 2 1 kg) were divided into 6 groups. Anesthesia was induced and maintained with halothane in 02.A cuffed endotracheal tube was introduced without the use of muscle relaxants, and breathing was controlled with a volume-limited respirator to achieve an end-tidal C02 (infrared analysis) of 4 to 5%. Intermittent end-tidal gas samples were obtained from the end of the endotracheal tube via a nylon catheter. Halothane concentration was measured with a Beckman LB-1 infrared analyzer. Esophageal temperature was measured and maintained between 36.5 and 38.5 C by external heating or cooling. MAC was determined as described previously, using tail clamp as the stimu1us.lO All measurements were made after 15 minutes at a constant end-tidal halothane concentration. Arterial blood for blood-gas analysis was drawn from a catheter inserted into the femoral artery. Using a 19-gauge needle, we punctured the cisterna magna a t the times indicated below to measure cerebrospinal fluid pressure and to obtain fluid samples for acid-base, osmotic and electrolyte determinations. Pco2 and pH were measured with standard electrodes. Osmolality was determined by the freezingpoint technic. Sodium and potassium con*MAC is the minimum alveolar concentration of anesthetic required to abolish movement in response to a painful stimulus in 50% of animals. It is an anesthetic EDEowhich ordinarily is unaffected by a variety of factors, including duration of anesthesia.10
405
centrations in blood and in cerebrospinal fluid were determined by flame photometry. Pressures in the femoral artery and the cisterna magna were transduced with Statham strain gauges and recorded with the ECG on a Grass polygraph. After induction with halothane, we determined MAC (control) and drew samples of blood and cerebrospinal fluid. In group 1 dogs (6 dogs), we then infused a solution containing 160 mEq/L of potassium chloride.We adjusted the infusion to the maximum permitted by alterations in the ECG and blood pressure. After 3 to 4 hours of infusion and again after 7 to 8 hours of infusion, we redetermined MAC and obtained blood and cisternal fluid. In a 2nd group ( 8 dogs), we examined whether changes in sodium altered halothane MAC. A control MAC was determined, and arterial blood and cerebrospinal fluid obtained for analysis. We then administered 10 mEq/kg/hr of a 510 mEq/L sodium chloride (3% NaCl) infusion to which we added 50 mEq/L of sodium bicarbonate and 10 mEq/L of potassium chloride. This solution was i n f w d for 4 hours. Between the 3rd and 4th hour, MAC was redetermined, and blood and cerebrospinal fluid samples again were obtained. After that, 1000 ml of 5% dextrose in H 2 0 were given IV along with 2000 ml of distilled H 2 0 instilled into the stomach via an orogastric catheter. After an additional 4 hours, we redetermined MAC, and blood and cerebrospinal fluid samples were drawn. Next) we examined the influence of changes in serum osmolarity achieved with nonelectrolytes on MAC and cerebrospinal fluid, electrolytes, and osmolality. In the 3rd group (3 dogs), we determined a control MAC and took arterial blood and cerebrospinal fluid samples. Then 4 g/kg/hr of mannitol were infused for 4 hours. MAC was redetermined in the 4th hour of infusion, and arterial blood and cerebrospinal fluid again were obtained for analysis. In the 4th group (6 dogs), after the determination of a control MAC and electrolytes and osmolality in serum and cerebrospinal fluid, 500 ml/hr of 25% dextrose were infused for 3 hours. MAC was redetermined in the 3rd hour, and blood and cerebrospinal fluid obtained. In the 5th group ( 5 dogs), we determined a control MAC, and took blood and cerebrospinal fluid samples. Then 1000 ml/hr of
406
Anesth Analg
CFS Electrolytes and Anesthetic Requirement
1274 dextrose were infused for 4 hours and MAC redetermined in the 4th hour. Blood and cerebrospinal fluid analyses were obtained after redetermination of MAC.
In the 6th group (5dogs), a control MAC was determined and blood and cerebrospinal fluid samples were drawn. We then administered 1000 ml/hr of 5% dextrose for 4 hours. MAC was redetermined, and blood and cerebrospinal fluid again were obtained during the 4th hour of infusion. Paired or unpaired Student's &tests were used to determine the significance of changes seen in MAC, electrolytes, and osmolality in serum and cerebrospinal fluid. A p value of less than 0.05 was accepted as significant.
RESULTS Group 1 (Potussium lnfmion1 - Serum potassium increased both a t the 4th and the 8th hour of infusion (table). cerebrospinal fluid potassium increased significantly but the increase was slight (11% at 8 hours compared to a 95% increase in serum). As might be expected, MAC did not change. Group 2 (Hypertonic Suline lnfusion 1Cerebrospinal fluid sodium increased 31 mEq/L (25%) in parallel with a 36 mEq/L increase in blood sodium. At the same time, cerebrospinal fluid potassium and osmolality increased 37 and 20%, respectively. The associated 43% increase in MAC was significant. Infusion of 5% dextrose accompanied by intragastric instillation of distilled H 2 0 eliminated all significant differences that had appeared at 3 to 4 hours. Note that n equals 5 for this group and that therefore the control values are slightly different from those listed under control in the table.
Group 6 (5% Dextrose Infusion)-MAC and serum and cerebrospinal fluid sodium and osmolality decreased significantly. In the 3rd through 6th groups a serum metabolic acidosis was present, probably secondary to dilution of serum base. This acidosis was not reflected in the cerebrospinal fluid, Cerebrospinal fluid acid-base status did not change significantly in any group. DISCUSSION Cerebrospinal fluid more closely represents brain extracellular fluid than plasma and hence we have emphasized the correlates of MAC with ionic changes in cisternal fluid. The blood-brain barrier appears to prevent alterations in some cerebrospinal fluid ions. Thus, in our experiment the ser u m potassium nearly doubled but cerebrospinal fluid potassium changed only slightly. That potassium does not easily cross the cerebrospinal fluid-brain barrier has been observed by other workers.11.1:3 As might be expected, in the absence of spinal fluid changes, MAC did not change with hyperkalemia. Cerebrospinal fluid potassium did change with other treatments. Both 12 and 25% dextrose infusions, mannitol infusion, and hypertonic saline infusion were associated with an increase in potassium. However, only the hypernatremia-associated increase in potassium altered MAC (table, fig 11.
Group 3 ( Munnitol Znfusion)-Although serum sodium decreased 10 mEq/L, cerebrospinal fluid sodium, potassium, osmolality, and MAC significantly increased, by about the same amount as in group 2. Group 4 (25% Dextrose lnfmion)--Serum sodium decreased 14 mEq/L while cerebrospinal fluid osmolality increased significantly (60 m mm, as in group 2 ) . Cerebrospinal fluid sodium rose slightly. MAC was not significantly increased. Group 5 (12% Dextrose infusion)-Serum osmolality increased and serum sodium decreased significantly but neither cerebrospinal fluid sodium nor MAC was changed. Cerebrospinal fluid osmolality increased significant 1y .
57.404-410, 1978
5% Dextrose I
2.2
3.0
3B
rnEq/L CSF K'
FIG 1. The correlation of changes in MAC with change in cerebrospinal fluid (CSF) potassium applied only to the results obtained with infusion of hypertonic saline (hypematremia) or mannitol (see table for mannitol data). Hypertonic (12 or 25%) dextrose infusions increased potassium without altering MAC while 5cj6 dextros: infusion decreased MAC without altering potassium. The bars at each point indicate the standard error for MAC and for potassium. T h e closed symbols indicate control values while the open symbols indicate the associated t.est values.
149 & 2 2.7
CSF
1 4 7 2 3 3.9 2 .2 301 2 2
154 2 1 3.0 2 .l 302 2 3
Blood
CSF
151 2 2 2 . 7 2 . l 3 0 2 2 2
CSF
4
146 ? 2 3.7 2 .3 301 & 4
&
Blood
.l 305
150 ? 2 2.6
CSJ? &
1 4 7 2 2 3 . 7 & .l 3 0 6 & 6
Blood
.l 3 0 0 2 4
147 2 2 2.7
CSF %
138 2 3 4.4 2 .2 301 2 7
Blood
&
2
1.09 2 .04
MAC
K+
14323
2 . 6 2 .l*
140 % 2* 6 . 8 2 .2*
NO+
-
-
Osm
1.07 & .05
MAC
1.04 & .06
.95 2 .07
.97 2 .04
1.13 2 .08
398 & 4
3.3 &
133 2 3% 2.6 & .l
276 % 3*
271 2 5* .79
&
.05*
358 ? 10:' .92 ? .07 .l':' 346 e 8%
119 & 3* 4.0 2 .2
155 & 2
.lo';:
1.04 2 .04
lo:*
370 2 14
.3* 359 &
106 & 1' 4.9 2 .4
166 2 3* 3.7
133 & 2'$ 3.8 2 .5
1.49 2 176 % 4* 3.7 2 .l* 379 & 6 +
123 2 3'< 4.5 2 .5
K+
8th hour
3.3 2 .3
3 . 2 2 .l
Recovery
142 2 3 2.7 2 . l *
140 & 3* 7.4 ? .5
NO+
lest
179 2 4* 4.8 2 .5* 373 2 8% 148& 2 1.00 2 .06 1.43 & .lo* .l 302 & 2 181 2 3* 3.7 + - .I;;: 361 + - 74: 161 & 2 &
143 2 2 3.7
Blood
.2 299
-
148 e 1 2.5 2 .l
CSF
&
-
148 2 1 3.8 2 .2
Osm
Blood
K+
4 t h hour
328 2 10
312 % 9
(n= 5)
-
-
0 sm
(n= 5)
~
1.02 2 .14
1.09 2 .04
MAC
;:Significantly different fmm control, 'Control" refers to values plus or minus t h e standard error obtained before infusions began, mhile "test" refers to values obtained 3 to 4 hours following the s t a r t of infusion and. in t h e case of groups 1 a n d 2. 7 t o U hours following t h e s t a r t of infusion. Electrolytes a r e mEq/I,, O s m i> mOsm/L, a i d M A C is psrcent halothane.
Group 6 5rk D / W ( n = 5)
Group 5 12% D / W ( n = 5)
Group 4 25(,4 D / W ( n = 6)
Group 3 Mannitol ( n = 3)
Group 2 Hypertonic saline (n = 8)
Group 1 H y perkalemia ( n = 6)
N.3+
Control
TABLE Summary of Results
408
Liley reported that an increase in osmotic pressure increased the frequency of s p n taneous discharges at the neuromuscular junction.13 This suggests that hyperosmolality increases nervous irritability and neurotransmitter discharge. Thus, a change in osmolality might influence anesthetic requirement. To distinguish between osmolality and sodium changes as the cause of the change in MAC, we tried to change amolality independently of sodium by infusing dextrose or mannitol. The success of this approach was determined by the ability of mannitol and dextrose to cross the bloodbrain barrier. One group of workers has suggested that an infusion of 4 g/kg/hr of mannitol for 4 hours injures the cerebrospinal fluid-brain barrier and allows mannitol to cross into the cerebrospinal fluid.14 Our results do not confirm this suggestion. Cerebrospinal fluid osmolality in group-3 dogs increased significantly, but the increase in cerebrospinal fluid sodium coupled with the associated negatively charged ions explains the osmolality change. In any event, since both sodium and osmolality increased, we could not estimate their relative effect on MAC. Although there is some limitation to the passage of dextrose into cerebrospinal fluid, the limitation is only partia1.l; We found (data not shown) that the cerebrospinal fluid dextrose equaled about 30% of the plasma concentration. Administration of either 25 or 12% dextrose (group 4 and 5) increased cerebrospinal fluid osmolality with either small (group 4 ) or no (group 5) increases in cerebrospinal sodium ( table, fig
T
/T
Hypertomc %lie
1
Anesth Analg
CFS Electrolytes and Anesthetic Requirement
I2 % Dextrose 5$Dex+,om
300
340
CSF
300
rnOsm/L
FIG 2. MAC correlated with the increase in osmolarity caused by hypertonic saline infusion or the decrease in osmolarity associated with 5 7 ~dextrose infusion. Administration of 12 or 25qc dextrose increased osmolarity without increasing MAC.
57:404.410, 197R
r MAC
1
T
1.0
I1 ~ , 8&/.,/5 % Dextrose A
I40
I60 mEq/L CSF Na’
I80
FIG 3. MAC consistently increased with an increase in cerebrospinal fluid sodium and decreased with a decrease in sodium.
2). MAC did not change remarkably in either group. Administration of 5% isotonic dextrose (group 6) reduced both cerebrospinal fluid sodium and osmolality. This dilution of cerebrospinal fluid sodium was associated with a reduction in MAC- Thus, in conflict with what might be predicted from Liley’s work, our results suggest that changes in osmolality do not exert a major effect on anesthetic requirement. Sodium does cross the cerebrospinal-brain barrier.1‘;-l9 Hypernatremia probably increased cerebrospinal fluid sodium not only by sodium crossing the blood-brain barrier, but also by dehydration secondary to administration of hyperosmotic solutions. Dehydration is reflected in the concomitant cerebrospinal fluid potassium and osmolality increase. The increased MAC in group 2 correlated well with cerebrospinal fluid sodium (table, fig 3 ) . The correlation of anesthetic requirement with changes in cerebrospinal fluid sodium also extended to the infusions of mannitol and 5% dextrose (table, fig 3 ) . Infusion of 25% dextrose produced a small (12 mEq/L) but significant increase in sodium. The associated small increase in the average MAC (0.07% halothane) was not significant. The other infusions produced changes in sodium and MAC that were too small to discern associated alterations (table). Our data suggest that changes in serum electrolytes or osmolality may be associated with changes in anesthetic requirement when they induce changes in brain sodium. Thus, many fluids that we (5% dextrose in H20, hypertonic saline, 5% dextrose in lactated Ringer’s solution) or our surgical colleagues
Anesth Analg 57:404-410, 1978
Tanifuji and Eger
(mannitol, distilled H20 for transurethral resection or gastric lavage) give may alter anesthetic requirement. I n the same way, disease states which increase or decrease cerebrospinal fluid sodium (eg, dehydration, diabetes insipidus) may alter anesthetic requirement. The relationship of MAC with sodium may be of theoretical interest. One explanation may be found in the work of Finck, Ngai, and Berkowitz.20 They suggested that anesthetics may act in part or whole by releasing enkephalin, a naturally occurring opiatelike substance found in both brain and spinal cord. Indeed they found that the administration of naloxone increased anesthetic requirement for a number of inhaled agents. The connection with sodium comes from the demonstration that sodium inhibits the binding of opiates to opiate receptors in the brain and thereby presumably interferes with the action of both endogenous and exogenous narcotics21 However, this effect of sodium is shared by and we have found (unpublished data) that lithium administration decreases MAC. Another explanation may lie in the potential effect of sodium on transmitter release. As noted earlier, it is known that an increase in extracellular sodium increases the transmembrane potential and the nerve action potential.] Diamond, Havdala, and Sabelli demonstrated that an increase in extracellular sodium antagonizes the depression of the nerve action potential produced by enflurane, halothane, or ketamine.?:]Release of neurotransmitter is directly related to the size of nerve action potential.? This suggests the possibility of a competitive effect of anesthesia and sodium at the nerve terminal. Diamond’s group also found that the threshold for depolarization was lowered by an increase in sodium.23 They demonstrated that the blockade of nervous transmission produced by halothane, enflurane, or ketamine at low sodium concentrations could be antagonized by raising the sodium concentration. Such an antagonism might apply both to the nerve terminal and to the postsynaptic membrane. The work of Shrivastav and his associates also may be pertinent to our findings. They found that trichloroethylene24or ketamine:: may decrease the peak of the nerve action potential by increasing resting sodium permeability and hence intracellular sodium. AS suggested in the introduction, this might impair transmitter release. A difficulty in
409
the interpretation of the importance of Shrivastav’s work is that the concentrations of anesthetic used were well beyond those required for anesthesia.
ACKNOWLEDGMENT Halothane ( FluothaneF) for this study was donated by Ayerst Laboratories.
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6. Ueda I, Shieh DD. Eyring H : Anesthe!ic interaction with a model ce11 membrane: expansion. phase transi!ion. and melting of !he leci!hin monolayer. Anesthesiology 41 :217-225, 19i4 7. Mel!zer SJ. Auer J : Physiological and pharmacological studies of magnesium salts. Am J Physiol 15:38i-405, 1906
8. Mannisto PT, Saarnivaara L: Effect of lithium and rubidium on the sleeping !ime mused by various intravenous anaesthe!ics in !he mouse. Br J Anaesth 48:185-189, 1 9 i 6 9. Tinker J H , Gandolfi AJ. Van Dyke RA: Elevation of plasma bromide levels in patients following halothane anesthesia. Anes!hesiology 44: 194-196, 1976 10. Eger I31 11, Saidman LJ. Brands!ater B: Minimum alveolar anesthetir concentm!ion: a standard of anes!hetic potency. Anesthesiology 26: i56-763,1965 11. Bekaert J, Demeester G: Influence of the potassium concentration of !he blood on !he potassium level of the cerebi-ospinal fluid. E x p Med Surg 12:480-501, 1954 12, Bradbury MWB, Davson H : The transport of potassium between blood. rerebrospinal fluid and brain. J Physiol (London) 181:151-1i4, 19%
13. Liley AW: An investigation of spon!aneous artivity at the neuromusciilar junc!ion of !he rat. J Physiol 132:656-666, I956 14. Stuar! FP, Tories E. Fletcher R, et al: Eff e d s of single. repeated and massive mannit01 infusion in !he dog: structural and fundional rhanges in kidney and brain. Ann Surg 172:190-204, 19iO
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CFS Electrolytes and Anesthetic Requirement
Anesth Analg 57:404.410, 1978
15. Fishman RA: Carrier transport of glucose hetween hlood and cerehrospinal fluid. Am J Physiol 206:836-844, 1964
21. Pert CB, Pasternak G, Snyder SH: Opiate agonists and antagonists discriminated by receptor hinding in brain. Science 182: 1359.1361, 1973
16. Schain R J : CSF and serum cation levels. Arch Neurol 11:330-333, 1964
22. Pert CB, Snyder SH: Opiate receptor hinding of agonists and antagonists affected differentially hy sodium. Mol Pharmacol 10:868-879, 1974
17. Pape LG, Katzman R: Effects of hydration on h h o d and cerebrospinal fluid osmolalities. Proc Soc Exp Biol Med 134:430-433, 1970 18. Bakay L: Studies in sodium exchange. Neurology 10:564571, 1960
23. Diamond BI, Havdala HS, Sahelli HC: Differential memhrane effects of general and local anesthetics. Anesthesiology 43:651-660, 1975
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25. Shrivastav BB: Mechanism of ketamine hlock of nerve conduction. J Pharmacol Exp Ther 201: 162-170, 1977
MYOCARDIAL CHANGES I N MALIGNANT HYPERTHERMIA Although considerable information is available about the structural and biochemical changes in the skeletal muscles of patients with malignant hyperthermia, little is known of the cardiac changes in this disease. However, ventricular fibrillation and cardiac arrest occur frequently. In 3 patients with malignant hyperthermia, contraction bands and foci of myofiberlysis were found in the heart at necrnpsy. Ultrastructurally, areas nf myofiber overstretching adjacent to contraction bands and foci of extensive myofiberlysis were associated with disruptions of the sarcolemma. Similar ultrastructural findings were seen in the skeletal muscles of these patients and may be responsible fnr the hyperkalemia which is a constant feature of nidignant hyperthermia. The ventricular arrhythmias frequent in this disease are likely the result of direct damage to cardiac muscle rather than secondary to eIevated plasma Ievels of potassium. (Fenoglio JJ Jr, Irey N S : Myocardial changes in mslignant hyperthermia. A m J Path01 S9:51-58, 1977)
