Part II, Chapter 10, Magnesium Deficiency in the Pathogenesis of Disease, by Dr. Mildred S. Seelig

Goldwater Memorial Hospital
New York University Medical Center
New York, New York
1980

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| Jacket | Preface | Contents | Introduction (Chapter 1) |
Chapter: | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 | 11 | 12 | 13 | 14 |
| Appendix | Bibliography (A-D), (E-K), (L-R), (S-Z) |

*All figures and tables for Chapter 10*

With such strong evidence that magnesium deficiency-or other factors that cause subnormal magnesium levels-can lead to functional and morphologic cardiovascular abnormalities, it is surprising that there has been so little clinical application of these findings. It is to be hoped that the detailed case reports published by Chadda et al. (1973b) and Iseri et al. (1975), in which they described rapid correction by magnesium of arrhythmias that had been refractory to the widely accepted therapeutic modalities, will stimulate others to consider magnesium treatment and evaluation of the magnesium status of patients with cardiac, and especially life- threatening arrhythmias. It must be cautioned that severe hypomagnesemia is not a necessary finding. For example, Chadda et al. (1973b, 1976/1980) found only slightly subnormal serum magnesium levels, but histories of diuretic intake and myocardial infarctions (which cause magnesium loss) in patients with a high incidence of ventricular ectopia. Iseri et al. (1975) reviewed the clinical states and drugs associated with magnesium deficiency and loss, and pointed out that magnesium deficiency can clearly exist without hypomagnesemia. They cited a reference (Loeb et al., 1968) that demonstrated that hypomagnesemia can predispose to arrhythmia (which eventually responded to standard therapy without magnesium repletion). Noting the rapid response to magnesium of hypomagnesemic arrhythmias reported by others (Scheinman et al., 1969; Rosefsky, 1972; Chadda et al., 1973a) they instituted magnesium therapy in refractory arrhythmic patients after taking a blood specimen for pretreatment magnesium values, and affirmed the rapidity with which the arrhythmias were corrected.

Unfortunately, magnesium determinations are rarely part of the routine electrolyte evaluation of patients with arrhythmia. Even when detected, its correction may be delayed until failure of classic approaches; addition of magnesium results in rapid amelioration of rhythmic disturbances (R. Singh et al., 1975). Among those who have diagnosed hypomagnesemia, electrocardiographic evaluation is reported only occasionally. Thus, there are no firm data at present as to the frequency with which both abnormalities coexist. In a pilot study, Chadda et al. (1977) found that 10 among 12 patients with hypomagnesemia (7 secondary to alcoholism, 2 secondary to malabsorption and intestinal fistulae, 2 as a result of postsurgery hyperalimentation, and 1 in chronic renal failure), 10 had cardiac arrhythmias. Seven had ventricular tachycardia, fibrillation or more than 6 premature beats (VPBs) per minute, or atrial arrhythmia with hypotension. All of the patients with VPBs had a prolonged QT interval. Two patients had electrical alternans. The serious arrhythmias of 4 of the patients had been unresponsive to any treatment other than magnesium. All of the arrhythmic patients improved when magnesium was given.

When one considers the unreliability of serum magnesium as an index of the cellular magnesium status, the difficulty of correlating (occult) magnesium deficiency with ECG abnormalities or predisposing cardiomyopathies can be readily appreciated.

In this section, attention is given to the dramatic responses of arrhythmias to magnesium therapy and to the conditions in which such responses have been described. Consideration is also given to the nature of the magnesium therapy, and to the differences in results obtained when it is used simply as a pharmacologic agent, and when it is given as sustained therapy (in which event one may presume that an underlying deficit may be repaired). It is possible that prophylactic long-term use of magnesium supplements, possibly from the beginning of life, might be preventative of the cardiomyopathies and arterial lesions that predispose to arrhythmias (supra vide), as well as of some skeletal and renal disorders (infra vide).

Intravenous use of magnesium to correct arrhythmias was demonstrated by Seekles et al., (1930), who found that it was useful in reversing arrhythmia caused by calcium treatment of the convulsions and tetany of cows with "grass staggers" of early lactation. This group soon demonstrated this disorder in cows that were hypomagnesemic and showed that it developed in areas and at times when there was a high potassium/magnesium ratio in their forage (Sjollema and Seekles, 1932). In a few years this syndrome was shown to be associated with cardiovascular lesions that involved the subendocardium and the myocardium, including the Purkinje cells (Moore et al. 1936). Thus, these studies of the correction by magnesium of calcium-induced arrhythmia might have been the result of correction of calcium-intensified magnesium deficiency. More recently, Ghana and Rabah (1977) have shown that magnesium reduces the vulnerability to electrically induced ventricular premature contractions (VPC) and of ventricular fibrillation (VP) of normal intact dogs, heart-lung preparations, and digitalized dogs (Table 10-1). Intravenous magnesium chloride solution, providing 100 mg of magnesium per kg of dog, increased the millivoltage tolerated by the intact dogs by 53% and over 100%, respectively, before they developed VPCs and VF. The heart-lung preparations tolerated 72% and 130% higher millivoltages before developing the VPCs and VF. Three of the digitalized dogs did not survive the VP phase before magnesium was to be given.

It is of interest that intravenous calcium, especially when given to patients with arrhythmias of digitalis toxicity, has had serious, sometimes catastrophic, effects (Lloyd, 1928; Bower and Mengel, 1936; Berliner, 1936; Golden and Brams, 1938). The potentiation of toxicity of cardiac glycosides, not only by calcium, but by other agents (e.g., catecholamines) that increase myocardial uptake of calcium suggest that potentiation of calcium influx into the myocardium by cardiotonic alkaloids (Review: Nayler, 1967) is potentially harmful. Cardiotonics simultaneously cause magnesium efflux from the myocardium (Hochrein et al., 1967; Wilke and Malorney, 1971) and inhibit magnesium-dependent cardiac mitochondrial and microsomal enzymes (Review: Seelig, 1972). Relevant to these findings is the observation that quinidine causes focal mitochondrial damage (Hiott and Howell, 1971) and that both magnesium and potassium chloride have significantly (p < 0.001) reduced cardiac necrosis caused by digitoxin (Savoie et al., 1969).

Noting the risk of using intravenous calcium in measuring circulation time, which even in noncardiac patients causes flattened or inverted T waves in 92% of the subjects, flattened or inverted P waves in 54%, and marked bradycardia in 67%, M. Bernstein and Simkins (1939a,b) contrasted the effects of magnesium as a circulation-time reagent. They investigated the electrocardiographic effects of 10 ml of 10% magnesium sulfate solution (100 mg of magnesium) in 100 patients: 66 with and 34 without cardiovascular disease. They found no deleterious effects on the heart. There were inconsistent ECG changes in 26 of the 66 cardiac patients during or after the injection that were limited to the T waves and the QRS complexes (usually increased amplitude). Comparable benign changes were seen in 10 of 34 noncardiovascular disease patients. They had undertaken the study because of the statement that had been made that "sudden death following the injection of a magnesium salt … is not an uncommon occurrence," and the demonstration (with massive doses of magnesium) that magnesium adversely affected cardiac rhythmicity (J. R. Miller and VanDellen, 1938). P. K. Smith et al. (1939) demonstrated, for example, that cardiac arrest could indeed be produced by magnesium, but not below serum magnesium levels of 27 to 44 mEq/liter. Thus, it is important to distinguish between pharmacologic doses of magnesium, such as are used in the treatment of arrhythmias, and toxic doses. Serum levels of magnesium should be kept below 5.5 mEq/ liter (Iseri et al., 1975; Iseri and Bures, 1978), which gives an ample safety margin. Only levels above 10 mEq/liter have been shown to cause toxicity (Review: Engbaek, 1952).

B. M. Cohen (1952), who reviewed digitalis toxicity and its treatment, summed up the arrhythmias produced (nodal and paroxysmal tachycardias, ventricular extrasystoles often producing bigeminy or trigeminy, and heart block) and mentioned contraindications of digitalis therapy, including paroxysmal ventricular tachycardia, and coronary insufficiency without cardiac failure. He also cited the risk of calcium therapy in digitalized patients and the additive toxic effects of digitalis and catecholamines. It is noteworthy that the arrhythmias described are also seen in magnesium deficiency and that magnesium deficiency or loss increases susceptibility to digitalis toxicity in animal and man (Vitale et al., 1961, 1963; Kleiger et al., 1966; Caddell, 1967; Wacker and Parisi, 1968; Ono, 1971/1973). Furthermore, patients with digitalis toxicity not infrequently have subnormal magnesium levels (Kim et al., 1961; Beller et al., 1974; R. Singh et al., 1976).

Magnesium's antiarrhythmic effects were first demonstrated in man in digitalis toxicity (Zwillinger, 1935). This effect has also been demonstrated experimentally (Zwillinger, 1935; Szekely, 1946; J. Stanbury and Farah, 1950; Szekely and Wynne, 1951; Gendenshtein and Karskaya, 1963; Bajusz et al., 1969; Seller et al., 1970a,b; Neff et al., 1972; Specter et al., 1975) and affirmed in man (Boyd and Scherf, 1943; Szekely, 1946; Zimdahl, 1946; Freundlich, 1946; Szekely and Wynne, 1951; R. Par sons et al., 1959; Michel, 1966; Kabelitz, 1968; Condorelli, 1971/1973; Lossnitzer, 1971a,b; Rotman, 1971; Iseri et al., 1975; R. Singh et al., 1976; Iseri and Bures, 1978). The long time lag between the first cluster of clinical reports and the more recent observations on magnesium's efficacy in digitalis arrhythmia and in other arrhythmias is probably a consequence of its early use only as a pharmacologic agent that had transient activity and occasionally caused increased irregularity of rhythm (B. M. Cohen, 1952). Since then, the substantial evidence that loss of magnesium from the myocardium can cause cardiomyopathies that predispose to arrhythmias justifies reexamination of how best to utilize magnesium in their treatment.

Electrocardiographic changes caused by coronary ligation in dogs have responded to intravenous infusion of magnesium salts. Harris et al. (1953) showed that the duration of ischemic tachycardia and ectopic rhythm was shortened in 46% of the dogs infused with magnesium as the sulfate and in 70% of the dogs infused with magnesium as the chloride, at a dose of 1 mEq/liter. Clark and Cummings (1956) found that each of three successive MgSO₄ infusions corrected the ischemic tachycardia and multifocal ventricular arrhythmia (J. R. Cummings, personal communication). Locke-Ringer solution lacking magnesium did not influence ischemic fibrillation, but when either 0.05 mEq or 2.0 mEq of magnesium was added-either to Ringer's solution or to 0.9% saline-there was protection against fibrillation. Dogs with persistent ventricular tachycardia and ectopic extrasystoles (after two-stage coronary ligation) responded to repeated injections (up to seven) of MgNa₂EDTA solution (50-100 mg/kg body weight) by a 25% decrease in heart rate, and sometimes by transitory restoration of the sinus rhythm on the day after the ligation. The effect of the infusions were sustained somewhat longer, but were still transient, two days after the ligation (Gendenshtein and Karskaya, 1963). The aspartate salts of magnesium and potassium, in combination, were protective against ischemic ECG changes in rabbits with coronary arterial ligation (Weber et al., 1958) and against ECG of asphyxia in guinea pigs (Hochrein and Lossnitzer, 1969)

Isolated hearts, under hypoxic conditions, have shown less reduction of systolic amplitude and other ECG changes of anoxia when suspended in fluids containing magnesium and potassium aspartates; chloride salts of the cations were less effective (Laborit et al., 1957; Weber et al., 1958; Trzebski and Lewartowski, 1959: LaMarche and Tapin, 1961; LaMarche et al., 1962; H. Rosen et al., 1964: LaMarche and Royer, 1965). Some of the benefit might reflect the coronary vasodilation shown to be produced by magnesium and potassium sulfate or chloride (Elek and Katz, 1942; Scott et al., 1961; Review: Haddy and Seelig, 1976/1979). The aspartate salts were more effective than the chlorides in the in vitro studies.

Having demonstrated in vitro that magnesium sulfate has coronary vasodilator activity, Elek and Katz (1942) recommended its use as a pharmacologic agent in paroxysmal tachycardia associated with myocardial ischemia. Boyd and Scherf (1943) corrected paroxysmal auricular tachycardia (PAT) by giving 10-15 ml of 15% MgSO₄ or 10 ml of a 30% solution intravenously (in 10 of 19 treatments). Comparable dosage was effective in 9 of 13 patients with PAT and in 1 with Wolff-Parkinson-White syndrome (Szekely, 1946), restoring sinus rhythm and decreasing the heart rate. The latter investigator noted that the patients most responsive to magnesium therapy were those who had advanced heart disease with congestive failure. One may speculate that such patients are likely to have received long-term diuretic and cardiotonic therapy, and thus to be most magnesium depleted. Neither group found any effect of magnesium on auricular flutter or fibrillation.

Despite these early promising results, and the experience of clinicians from the British Commonwealth (England, South Africa, Australia, and England: Malkiel Shapiro et al., 1956; 1960; Malkiel-Shapiro, 1958; R. S. Parsons, 1958; Parsons et al., 1959, 1960, 1961; Agranat, 1958; Marais, 1958; Teeger, 1958; Anstall et al., 1959; Browne, 1961, 1963, 1964a,b; Hughes and Tonks, 1965; Tonks, 1966) with the efficacy of long-term treatment of patients with acute or chronic IHD (rationale based on magnesium's effects on blood coagulation and lipids), the clinical use of magnesium in cardiovascular disease has been slow to gain acceptance in America. It has been utilized, usually with potassium, with and without heparin, and as organic salts (e.g., nicotinate and aspartate) parenterally (with and without glucose and insulin) immediately after infarction, and orally in the management of postinfarction patients and those with angina pectoris. Such use has been described in studies from the European continent (Hoffman and Siegel, 1952; Laborit et al., 1958; Melon, 1960; Thurnherr and Koch, 1962; Larcan, 1963; Perlya, 1965; Kanther, 1966; Kenter and Falkenhahn, 1966; Rigo et al., 1965; Köhler, 1966; Laborit, 1966; Larcan, 1966; Maté et al., 1966; Michel, 1966; Nieper and Blumberger, 1966; Pillen, 1966; Stepantschitz and Fröhlich, 1967; Savenkov et al., 1971). Most of the reports have been uncontrolled clinical trials, sometimes large series of cases that were compared with prior series treated identically except for the magnesium (and potassium) salts. (Representative treatment regimens are entered on Table 10-3 and Table 10-3 continued.)

Whether the combination of magnesium and potassium aspartate salts, given in high doses for treatment of the acute infarction and then followed by prolonged oral therapy for indefinite periods, provides better results than does the inorganic sulfate, which was somewhat similarly used only in the South African and Australian studies, cannot be averred. The studies evaluated different parameters; comparably better results were obtained with prolonged than with short-term therapy. Nieper and Blumberger (1966) refer to a controlled study with the mixture of magnesium and potassium aspartates in 45 patients with acute myocardial infarction (Tapin, 1962). Classical anticoagulant and supportive therapy was provided the 25 control patients; 2 g of magnesium and potassium aspartate were added to the daily infusions of the 20 patients in the test group until infusions were discontinued, at which time the patients were given the same daily dosage orally. [Nieper and Blumberger (1966) commented that their own experience indicates that 5 g daily in 250 mg of 5% glucose, given by slow intravenous infusion, for 4 to 5 days is preferable, to be followed by 2 to 4 g daily orally thereafter.) Nonetheless, Tapin (1962) found that, even with the low dosage used, his magnesium and potassium aspartate treatment group had a somewhat lower death rate in the hospital (40% versus 56% among those on standard therapy). The real difference was manifest among the survivors (6 months to 2 years follow-up). The magnesium and potassium aspartate treated group showed complete recovery in 45%; only 8% of the controls recovered completely. Pillen (1966) and Nieper and Blumberger (1966), using the higher dosage regimen routinely in their acute-infarct patients, found good to excellent results in 16 of 19 patients, and recommend immediate intravenous administration of magnesium and potassium aspartate as part of the emergency treatment, even before the patient reaches the hospital. They found rapid improvement of the ischemic ECG (within 12-24 hours), as well as rapid decrease of pain, most patients requiring no analgesic therapy.

Stepantschitz and Frohlich (1967) compared the outcomes in three groups of patients hospitalized for six weeks after an acute myocardial infarction: Group I (114 patients) received standard supportive therapy that included oxygen, sedation, alkaloids, treatment of shock with corticosteroid and epinephrine, and antiarrhythmia agents as necessary. Group 11(123 patients) were also given anticoagulants. Group III (100 patients) were given magnesium and potassium aspartate in addition to the therapeutic regimen given group II. Each patient in group Ill was given 6 mEq of magnesium and potassium and 12 mEq of aspartate in 250 ml of 5% levulose once or twice daily for three weeks, and the same dosage for the remaining three-week period of hospitalization. The death rate in group I was 46.5%, versus 13 and 15% in groups II and III. However, in noting the comparable mortalities in the groups receiving anticoagulants (II) and magnesium and potassium aspartate (III), the authors noted that the patients in group III had had 13 times as many recurrent infarctions as had the other two groups, and thus had the poorest prognosis. They tabulated the criteria for the effects of treatment (Table 10-4) and pointed out that the most striking advantage of the magnesium and potassium aspartate therapy was in the time taken to achieve complete freedom from pain (average of 5.3 days, versus 16.8 and 14 days in groups I and II0. The average time taken for the ECG to return to near normal was 15.5 days in group III, versus 22.3 and 23.7 days in groups I and II. Complete involution of the ECG signs of infarction occurred in 34% of the patients in group III, and in 11.4% and 17.9% of those in groups I and II.

Using the transcardiac iontophoretic method of giving magnesium to patients with myocardial infarction, Köhler (1960) found complete to almost complete relief of pain in 88 of 100 patients, and marked improvement in 12, as compared with complete relief in none, and marked to almost complete relief in only 27 who received placebo iontophoresis. In the remaining placebo group, 34 were unchanged or worse and 36 showed only slight improvement. He later commented (Kohler, 1966) that the iontophoretic procedure carries in only the cation. Kucher (1966), using the same procedure, but with both magnesium and potassium salts, reported that 180 to 184 patients (classified as angina pectoris with myocardial degeneration) improved, and all 22 patients who had recent infarctions improved. Among those who had refractory auricular fibrillation, extrasystoles, or paroxysmal tachycardia, 9 of 16 improved.

Laborit (1958) considered hypertonic glucose solutions useful in attaining a normal myocardial electrolyte gradient, (for repolarization) and recommended the use of aspartate salts of Mg + K. Sodi-Pallares et al., (1962, 1966, 1979) suggest the addition of insulin to reverse the ECG signs of ischemia. Kones (1975) has evaluated the clinical response of patients with infarction and reported that glucose-insulin- potassium therapy is a useful therapeutic adjunct. Opie and Owen (1976) have provided experimental evidence that such treatment increases the arteriovenous coronary difference of glucose, decreases the free fatty acids, accelerates the fall of the epicardial ST segment, and prevents the small rise in the ST segment in the peri-infarct and nonischemic zones. Gavrilescu et al. (1974) have shown that slow (over 1-hour period) i.v. infusion of 3 g of potassium and magnesium asparate in 200 ml of physiological saline lowers the elevated levels of free fatty acids that develop during the first hour after an acute myocardial infarction (p. 225).These findings support the contention that such treatment has beneficial effects on tissue metabolic, histologic, and electrocardiographic criteria of ischemic damage. In commenting on Sodi-Pallares' and Opie's findings in the clinical and experimental situation, and Sodi-Pallares' (1976) reminder that diuretics and antiarrhythmic therapy are contraindicated with the polarizing treatment, Bing (1976a, b) observed that the metabolic findings with this form of therapy might well provide a piece of the Rosetta stone. He indicated, however, that until the etiology of ischemic heart disease can better be defined, it will continue to be difficult to bridge the gap between fundamental and applied knowledge.

The data presented in this volume provide considerable evidence that cellular magnesium deficiency can be another key to the etiology of ischemic heart disease and other cardiomyopathies. Since administration of insulin and glucose has been shown to accelerate the uptake of ²⁸Mg by the heart more than twofold (Aikawa, 1960a), and the magnesium ion seems to be essential for maintaining tissue response to insulin (G. Bhattacharya, 1961), addition of magnesium to the polarizing solution would seem advisable. It is provocative that Bajusz (1964, 1965b) found that the partially protective effects of either magnesium and potassium chlorides or aspartates were markedly increased by simultaneous administration of glucose and insulin. Another justification for including magnesium in the polarizing solution is its requirement for the enzyme systems necessary for accumulation of potassium against a concentration gradient (Review; Seelig, 1972).

A metabolic approach to the treatment of endomyofibrosis of the adult (with abnormalities of the ST segment and Q wave) incorporated magnesium and vitamin B₁ as well as insulin, glucose, and potassium, to enhance glycolytic metabolism (Michon et al., 1959). Larcan (1966) later reiterated the value of this approach, using cocarboxylase (a B₁ metabolite) instead of thiamine in the treatment of patients with myocardial infarction. He stressed the importance of including magnesium. He reproduced representative ECGs from representative cases from his series of 40 cases, and commented that most striking was the much more rapid analgesic effect in the metabolically treated patients than in a control group that was treated by bed rest, anticoagulants, and opiates. Asthenia was also notably diminished, and the ischemic ECG changes regressed rapidly, the improvement beginning as early as four hours after the first ECG on hospitalization, and being definitive by the end of the first to second day of the infusions.

In most of the clinical trials, magnesium sulfate has been the salt used, and in the United States it is the only readily available parenteral preparation. Ischemic arrhythmia in dogs responded somewhat better to magnesium chloride than to magnesium sulfate at a 1 mEq/liter dose of magnesium (A. Harris et al., 1953). However, the numbers were too small for significance to be determined. Selye (1958d,) showed that not only phosphate, but also sulfate, sensitizes the heart to cardiopathic agents, whereas the chloride (of magnesium or potassium) is protective. He found no superiority of the aspartate or orotate salts of magnesium and potassium to the chloride salts as cardioprotective agents in his experimental models (Selye, 1958g). More recently a hydrochloride salt of magnesium and potassium aspartate has been investigated, and found to be better absorbed and utilized, and to be more effective than the aspartate salts in experimental cardiomyopathic models (Classen et al., 1973, 1975, 1976, 1978; Ebel et al., 1975). Neither magnesium sulfate nor magnesium aspartate were effective against cardiac necrosis induced by epinephrine plus a mineralocorticoid, whereas magnesium chloride and magnesium aspartate hydrochloride each exerted significant protective effects (Classen et al., 1975, 1978). These investigators concluded that it is necessary to correct, not only the magnesium deficit, but the hypochloremic alkalosis in metabolic myocardial necrosis. Lehr et al. (1972) concur that it is necessary to provide both magnesium and chloride to protect against experimental myocardial necrosis of widely different natures (Lehr, 1965, 1969; Lehr et al., 1966).

It is important to consider all of the positive and negative findings from animal and human studies in determining a safe, effective approach to the treatment of cardiomyopathic disease, whether of ischemic or other origin. Because magnesium deficiency or loss from the myocardium has been repeatedly implicated in experimental cardiomyopathy, and because magnesium is cardioprotective, it should be included in treatment programs, such as in the polarizing treatment. Sodi-Pallares (1969) cautions against the use of diuretics and corticoids (which cause loss of magnesium, as well as of potassium) and such inotropic drugs as digitalis, quinidine, and catecholamines, unless there is pulmonary edema or atrial fibrillation and ventricular tachycardia. Since inotropic drugs and some diuretics (e.g., thiazides) increase calcium retention and, in the case of the glycosides and catecholamines, increase myocardial calcium uptake and lipolysis, caution should also be exercised in treating hypocalcemia of cardiac patients with intravenous calcium salts. Potassium chloride is readily available and should certainly be included in the therapeutic regimen. (The author suggests that it be used with magnesium in a polarizing solution incorporating dextrose, water, and insulin.) Unfortunately, in the United States, magnesium is available for parenteral use more readily as the sulfate than as the chloride. Perhaps the aspartate-HCl salt of magnesium will become available in the United States, as it is in Europe.

Table 10-3 indicates the therapeutic regimens that have been effective in the treatment of the acute ischemic event and in hypomagnesemic arrhythmia. In open-heart surgery, magnesium has been a useful additive to the pump-prime (optimum concentration to be proved, supra vide) and has been used as an intravenous bolus (0.1 g/kg) to facilitate postoperative defibrillation (Buky, 1970). Magnesium chloride (100 mg Mg) has also been recommended, pre- and postoperatively, to prevent arrhythmias (Khan et al., 1973; Holden, 1978). The emergency therapeutic dosage of magnesium, as described by Iseri et al. (1975) is recommended, with the modification that after the bolus of magnesium, the maintained infusion should be 5-10% dextrose in water plus insulin (0.1 unit/g dextrose), and potassium (3-6 mEq) and magnesium (3-6 mEq) as the chloride or aspartate hydrochloride, if available. Possibly, the water-soluble B vitamins and vitamin C should be added to the infusion in "stress-formula" concentrations. Investigations are required to determine the optimal formulation.

(include the word "jacket" to search only in this book)

| Jacket | Preface |w Contents | Introduction (Chapter 1) |
Chapter: | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 | 11 | 12 | 13 | 14 |
| Appendix | Bibliography (A-D), (E-K), (L-R), (S-Z) |

*All figures and tables for Chapter 10*