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Chapter 7

Battle Casualties in Korea: Studies of the Surgical Research Team, Volume IV

The Phosphorus: Nonprotein Nitrogen (P:NPN) Ratio in Plasma as an Index of Muscle Devitalization During Post-traumatic Oliguria*

Major William H. Meroney, MC, USA

During the course of management of war casualties with oliguria, it was noted that inorganic phosphorus concentration in plasma rose to higher levels earlier in those patients with necrotic muscle wounds. It was expected that nonprotein nitrogen concentration in plasma also would rise at a greater rate when necrotic tissue was present, but it was not observed to do so. The rise in concentration of phosphorus out of proportion to nonprotein nitrogen appeared to be associated consistently with muscle necrosis. On several occasions the presence of muscle necrosis deep in a wound which appeared healthy on the surface was first suspected from a rise in the ratio of phosphorus to nonprotein nitrogen (P:NPN) in the plasma.

In order to test the validity of this clinical observation, the records of all the oliguric patients admitted to the Renal Insufficiency Center in Korea were reviewed. The purpose of this report is to relate these chemical and clinical findings in 28 selected patients and to propose the P:NPN ratio in plasma as a useful aid in the recognition of devitalized muscle during post-traumatic oliguria.

Clinical Material and Methods

Twenty-eight patients were selected from a larger series on the basis of the following criteria:

    (a) Renal insufficiency following trauma in young men who were presumably normal prior to injury.

    (b) Urine flow less than 500 cc./24 hours.

    (c) No other significant loss of fluid or non-volatile solutes.

    (d) Plasma NPN greater than 100 mg./100 cc.

    (e) Not yet subjected to hemodialysis by the artificial kidney.

    (f) No visible discoloration of plasma.

    (g) NPN and P determined on the same specimen of plasma.

    (h) Clinical evaluation by someone other than the author: one not aware of the chemical relationships to be considered.


*Previously published in Surgery, Gynecology and Obstetrics 100: 309, 1955.


116

On the basis of clinical evaluation alone, all of the patients who fulfilled the above requirements were divided into four groups:

    Group I. Massive necrotizing myositis which could not be excised completely or remained unrecognized ante mortem. All of these patients followed a characteristic clinical course of progressive mental torpor, disorientation, and hypotension culminating in death (cases #91, 93, 97, 108, 115, 121, 129, 132, 133, 137).

    Group II. Necrotizing myositis which was completely excised or amputated (cases #92, 104, 110, 130, 135).

    Group III. Superficial infection of large muscle wounds, controlled with conservative measures (cases #87, 95, 96, 102, 125, 127).

    Group IV. No apparent involvement of muscle but may have had severe, even fatal, infection or trauma of other tissues (cases #98, 107, 113, 114, 119, 128, 136).

Chemical methods: Nonprotein nitrogen by the method of Folin and Wu.1 Potassium by the flame photometric method of Hald.2 Inorganic phosphate by the method of Fiske and Subbarow.3 Other phosphorus fractions were not measured.

Chemical Findings and Discussion

The plasma values for nonprotein nitrogen, potassium and inorganic phosphates are listed in Table 1. The time scale is based upon the number of days after wounding, since the exact time of onset of oliguria was not always known. When a patient underwent hemodialysis, the relationships of the plasma chemicals were altered and the subsequent values are not included in the table.

The average of the daily NPN concentrations for all of the patients progresses by a rather regular increment each day. The daily average for each group similarly increases stepwise, and when these values are plotted against time they fall on a relatively straight line (Fig. 1). There is little difference among the daily averages of the four groups, and there is no significant difference between the average of the patients with and without myositis.

On a particular day the NPN concentrations vary considerably from one patient to another regardless of group; yet the successive daily values for many patients progress more or less regularly. For instance, patient #110 (see Table 1) has a concentration of 106 mg./100 cc. on day 3 as compared with a group average of 140 and an over-all average of 158; yet this patient's concentration of NPN increases by


117

FIGURE 1. The average NPN concentration for each clinical group, plotted against time in days following wounding.

increments which are regular and which parallel the average increments for the group on subsequent days. It would appear that such a patient is displaced forward on the time scale and that day 3 actually is day 1 or 2. It is likely that such errors occurred, because the chart is constructed as if oliguria dated from injury. The regularity of the daily increase in NPN concentration in all the patients, as illustrated by the linearity of the curves in Figure 1, suggests that the rise in NPN concentration per day is related to the duration of oliguria but not to the presence or degree of tissue necrosis.

The potassium which accumulates in the plasma during oliguria, when no potassium is administered, represents loss of potassium from the tissues. The food intolerance usually accompanying acute uremia results in a caloric deficit, and tissues are catabolized to supply nutritional requirements. The accumulation of potassium in the plasma can be minimized when carbohydrate feedings or infusions are provided.4-7 When additional cells are devitalized by trauma, infection, or other physical or chemical agents, the additional potassium released to the plasma may exceed the capacity of the body to remove


118

    Table 1. Plasma Chemical Data
    (NPN and P are expressed in mg./100 cc., K in mEq./L.)

Post-wound Day

2

3

4

5

Case No.

NPN

K

P

NPN

K

P

NPN

K

P

NPN

K

P

Group I

    91

 

124

 

7.2

 

6.7

 

176

 

7.1

 

 

211

 

5.6

 

 

249

 

7.2

 

11.9

    93

 

 

 

102

7.9

 

150

7.8

12.3

 

 

 

97

 

 

 

167

6.0

7.8

191

5.9

 

250

6.4

11.5

108

 

 

 

 

 

 

105

6.5

9.5

182

7.3

9.8

115

106

6.5

5.0

119

5.9

6.0

136

6.3

7.3

180

7.6

11.7

121

 

 

 

139

5.0

4.3

188

4.7

12.9

 

 

 

132

134

6.5

8.5

178

6.6

12.3

255

7.5

16.3

 

7.1

16.5

133

130

7.0

5.3

152

7.3

11.3

220

8.7

14.4

257

8.8

16.8

137

129

8.6

11.4

 

 

 

 

 

 

 

 

 

129

196

8.3

7.0

261

6.5

18.7

 

 

 

 

 

 

Total

819

44.1

43.9

1294

52.3

60.4

1456

53.0

72.7

1118

44.4

78.2

No.

6

6

6

8

8

6

8

8

6

5

6

6

Aver.

136

7.4

7.5

162

6.5

10.1

182

6.6

12.1

224

7.4

13.0

Group II

    92

 

 

 

 

171

 

8.3

 

8.8

 

190

 

8.1

 

10.4

 

231

 

7.9

 

12.6

104

 

 

 

 

 

 

206

8.4

14.6

235

7.6

14.0

110

 

 

 

106

6.1

6.0

138

5.6

7.9

166

5.2

8.6

120

104

4.5

 

131

4.8

5.1

166

5.3

6.8

197

6.4

 

135

114

8.1

6.0

151

8.0

10.9

 

 

 

 

 

 

Total

218

12.6

6.0

559

27.2

30.8

700

27.4

39.7

829

27.1

35.2

No.

2

2

1

4

4

4

4

4

4

4

4

3

Aver.

109

6.3

6.0

140

6.8

7.7

175

6.9

9.9

207

6.8

11.7


119

Table 1. Plasma Chemical Data (cont.)
 

Post-wound Day

2

3

4

5

Case No.

NPN

K

P

NPN

K

P

NPN

K

P

NPN

K

P

Group III

    87

 

 

 

 

 

 

 

151

 

7.0

 

 

182

 

7.1

 

11.3

95

102

5.2

5.8

173

5.3

 

192

6.0

 

239

6.8

7.0

96

112

5.0

5.0

120

5.4

 

 

4.6

 

200

5.1

 

102

 

 

 

163

7.4

8.5

189

6.7

9.3

267

8.3

12.6

125

 

 

 

167

6.9

5.7

213

5.7

8.2

266

6.8

9.7

127

 

 

 

 

 

 

147

7.4

6.4

177

6.9

7.2

Total

214

10.2

10.8

623

25.0

14.2

892

37.4

23.9

1331

41.0

47.8

No.

2

2

2

4

4

2

5

6

3

6

6

5

Aver.

107

5.1

5.3

156

6.3

7.1

178

6.2

8.0

222

6.8

9.6

Group IV

    98

 

 

 

 

177

 

5.5

 

5.8

 

209

 

7.1

 

9.1

 

245

 

7.0

 

9.9

107

 

 

 

177

7.4

7.3

231

7.9

8.3

 

 

 

113

 

 

 

170

3.2

 

196

3.5

7.2

214

5.4

6.1

114

 

 

 

 

 

 

131

4.6

4.8

 

4.3

7.4

119

145

6.9

3.6

176

6.5

3.9

220

5.2

3.5

295

8.3

3.2

128

113

8.2

5.5

 

 

 

 

 

 

 

 

 

136

 

 

 

151

5.2

6.2

173

5.1

6.5

247

5.4

7.5

Total

258

15.1

9.1

851

27.8

23.2

1160

33.4

39.4

1001

30.4

34.1

No.

2

2

2

5

5

4

6

6

6

4

5

5

Aver.

129

7.6

4.6

170

5.6

5.8

193

5.6

6.6

250

6.1

6.8

Over-all Total

1509

82.0

69.8

3327

132.3

128.6

4208

151.2

175.7

4279

142.9

195.3

No.

12

12

11

21

21

16

23

24

19

19

21

19

Aver.

126

6.8

6.3

158

6.3

8.0

184

6.3

9.2

225

6.8

10.3


120

it.8 Muscle cells are rich in potassium, and the degree of devitalization of muscle might be expected to correlate well with the concentration of plasma potassium. Indeed, the patients in Group I did tend to have higher values initially, but the concentration did not continue to rise progressively. Because of the lethal properties of potassium, maximal efforts were directed toward its control, and the over-all average plasma level was no higher on day 5 than on day 2 (Fig. 2). If measures for the control of hypergalemia9, 10 are employed, the concentration found after treatment will be of little value in the estimation of cell destruction.

FIGURE 2. Average daily potassium concentration compared with NPN on successive days.


121

Plasma phosphate, like NPN, is little affected by the non-dialyzing measures which are directed toward the control of potassium. Phosphorus is largely an intracellular substance, and when it is delivered to the plasma, effective means to cause it to be re-incorporated into tissue have not been demonstrated. Except for the small amounts of phosphorus which are removed from the plasma under the influence of carbohydrate feedings or infusions,11 that which is in plasma remains there until renal function is recovered or hemodialysis is instituted. The plasma level of phosphate should then be a gauge of the extent of devitalization of tissue which is rich in phosphate. Such a tissue is muscle, and Figure 3 demonstrates the average plasma phosphate concentration for each of the four groups representing clinical estimates of degrees of muscle damage. Group I, which is constituted of patients with massive muscle necrosis which was fatal, shows the highest average value; Group II, which is constituted of patients with massive muscle necrosis which was extirpated before it progressed to a lethal degree, shows the next highest value; Group III, which is constituted of patients with superficial muscle infection which was controlled by conservative treatment, shows the next highest value; and Group IV, representing varying degrees and types of trauma and infection but no gross muscle damage, shows the lowest value.

As time passed, myositis appeared and progressed, and the plasma phosphate concentrations for patients with and without myositis diverged. As shown in Table 2, the difference between the mean phosphate values of the patients with and without myositis is not signifi-

Table 2. Plasma Phosphorus (mg./100 cc.) in Patients With Myositis (Groups I and II) Compared With Patients With No Myositis (Groups III and IV)

Post-trauma Day

2

3

4

5

Myositis

    No.

7

10

10

9

Mean

7.1

9.1

11.2

12.6

SD

2.2

4.5

3.3

2.8

No Myositis

    No.

4

6

9

10

Mean

5.0

6.2

7.0

8.2

SD

0.98

1.6

2.0

2.7

Difference between Means

2.1

2.9

4.2

4.4

Standard Error of Difference

1.0

1.6

1.2

1.3

P

>.05

>.05

<.01

<.01


122

FIGURE 3. The daily average inorganic phosphate concentration for each clinical group, plotted against time in days following wounding.

cant on days 2 and 3 but is significant on days 4 and 5. The difference might have been more striking if five patients with high values had not been dropped from the myositis groups because of death or hemodialysis.

It is noted in Figure 3 that all of the groups show progressive daily increases in concentration, and the average value for each group is higher on day 3 than the average value for the group next higher on the graph on day 2. A value which would be acceptable in Group IV on day 4 would fall into the Group I range if it occurred on day 2. Therefore, in order to assess a particular value, the factor of time must


123

be considered. As previously noted, the duration of oliguria is not always known. Inaccuracies of immediate recognition and recording of the onset of oliguria are not uncommon in civilian as well as military situations. Under these conditions, if the NPN is used as a unit of time, the rise in phosphate concentration may be related to NPN concentration. Both NPN and phosphate concentrations rise progressively, and the average values rise together (Table 1). In these patients the rise in NPN is related to time, not muscle damage; the rise in phosphate is related to muscle damage and also to time. The degree of muscle damage should then be reflected by the degree of phosphate rise per unit NPN. Figure 4 demonstrates that the relation

FIGURE 4. The daily average inorganic phosphate concentration for all patients plotted against time and against NPN, indicating that NPN can be used as a unit of time.


124

of phosphate concentration to time is practically identical with its relation to NPN concentration.

The highest P:NPN ratio for each patient is plotted in Figure 5. The highest ratios occur in Group I (mean 0.071), the lowest in Group IV (mean 0.039) and the intermediate in Groups II and III. All the patients with myositis, Groups I and II, were compared with all the patients with no myositis, Groups III and IV. Thirteen of the fifteen patients with myositis have ratios above 0.05; 10 of the 13 patients with no myositis have ratios below 0.05 (P <.01).

FIGURE 5. The highest P:NPN ratio for each patient. Lines are drawn at ratios 0.04, 0.05 and 0.06 to show the degree of phosphate rise allowed to maintain the same ratio at different levels of NPN.

After this association of a high P:NPN ratio and muscle necrosis was observed in several patients, and a much lower ratio was observed in several patients with massive trauma and fulminating infections of abdomen and thorax, the presence of muscle necrosis was predicted from the P:NPN ratio alone. Each such attempt was successful, and the chemical changes sometimes antedated the clinical changes by several days. Surgeons who are confronted with the problem of distinguishing viable from non-viable muscle may find the P:NPN ratio a helpful guide in oliguric patients.


125

This relationship should not obtain unless severe oliguria is present; otherwise the phosphate which is released from muscle would be excreted in the urine. Also, a patient with a generalized disease of which renal insufficiency is but one component may show a great rise in plasma P:NPN ratio without muscle necrosis. In such a patient the increased release of phosphate from tissues is a reflection of catabolism in many areas. In oliguria secondary to trauma and shock, however, there appears to be less generalized catabolic response which causes a release of phosphate from tissues, and an increase in the P:NPN ratio should prompt the surgeon to re-examine all wounds of muscle.

Summary and Conclusions

The relationships between the rates of accumulation of plasma NPN, potassium and inorganic phosphate were examined in 28 severely wounded patients with post-traumatic renal insufficiency. The patients were divided into four groups on the basis of the presence or degree of devitalization of muscle, and the clinical evaluations were compared with the chemical findings.

NPN in plasma was found to rise at a fairly regular rate regardless of the type or amount of tissue destroyed. Plasma potassium concentration was reduced by vigorous treatment, and the post-treatment value bore little relationship to muscle damage or the other chemicals. Plasma phosphate rose more rapidly and to higher levels in patients with greater muscle damage. Since there are no standards of reference for the levels to which phosphate would rise in the absence of muscle damage in a given time, and the duration of oliguria in a particular patient may be unknown, the NPN can be used as a unit of time to which the phosphate can be related.

The P:NPN ratio can be used as an index of the degree of muscle destruction. A ratio above 0.05 indicates muscle damage, and a ratio rising above 0.06 should direct suspicion toward a large and potentially lethal area of muscle necrosis which may not be apparent on the wound surface.

Acknowledgments

The surgical procedures and evaluations were performed by Major H. H. Balch and Captain Y. Sako, U. S. Army, and Lieutenant C. E. Catlow, U. S. Navy.

The laboratory procedures were performed by Corporals J. T. Mackemull and B. F. Pease.


126

References

1. Folin, Otto, and Wu, Hsien: A System of Blood Analysis. J. Biol. Chem. 38: 81, 1919.

2. Hald, P. M.: The Flame Photometer for the Measurement of Sodium and Potassium in Biological Materials. J. Biol. Chem. 167: 499, 1947.

3. Fiske, C. M., and Subbarow, Y.: The Colorimetric Determination of Phosphorus. J. Biol. Chem. 66: 375, 1925.

4. Welt, L. G., and Peters, J. P.: Acute Renal Failure: Lower Nephron Nephrosis. Yale J. Biol. and Med. 24: 220, 1951.

5. Darrow, D. C.: Medical Progress: Body Fluid Physiology: The Role of Potassium in Clinical Disturbances of Body Water and Electrolytes. New Eng. J. Med. 242: 978, 1014, 1950.

6. Stock, R. J.: Acute Urinary Suppression: Observations in Twenty-two Patients. Am. J. Med. 7: 45, 1949.

7. Borst, J. G. G.: Protein Katabolism in Uremia: Effects of Protein-free Diet, Infections, and Blood Transfusions. Lancet 1: 824, 1948.

8. Fenn, W. O.: The Role of Potassium in Physiological Processes. Physiol. Rev. 20: 377, 1940.

9. Hopper, J., Jr., and Partridge, J. W.: Anuria and Oliguria: Treatment by Conservative Means, Case Report, with Determination of Blood Volume and Na24 Space. Calif. Med. 73: 42, 1950.

10. Meroney, W. H., and Herndon, R. F.: The Management of Acute Renal Insufficiency. J. A. M. A. 155: 877, 1954.

11. Pollack, H., Millet, R. F., Essey, H. E., Mann, F. C., and Bollman, J. L.: Serum Phosphate Changes Induced by Injections of Glucose into Dogs under Various Conditions. Am. J. Physiol. 110: 117, 1934.