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Rhabdomyolysis after Bariatric Surgery Décio Alexandre de Freitas Carvalho, MD; Antonio Carlos Valezi, PhD; Edvaldo Macedo de Brito, MD; José Carlos Lacerda de Souza, MD; Antonio César Masson, MD; Tiemi Matsuo, PhD* Department of Surgery and *Department of Mathematics, Londrina State University, Londrina, Brazil

Background: Rhabdomyolysis is a potential threat after bariatric surgey. The severity ranges from asymptomatic elevations of serum muscle enzyme levels to life-threatening cases associated with muscle necrosis, compartment syndrome, acute renal failure and cardiac arrest. Methods: We studied 98 consecutive obese patients who underwent primary uncomplicated bariatric surgery during a 1-year period. A database was created for all patients (sex, age, BMI, duration of the operation); serum creatinine phosphokinase (CPK) was systematically measured before surgery and on the first and second postoperative day. Results: The study sample consisted of 35 males (35.7%) and 63 females (64.3%) with preoperative CPK level 156.6 ± 41.1 U/L (40 to 220), 24 hours postoperatively 1,075.2 ± 596.5 U/L, (85 to 2,790 U/L) and 48 hours postoperatively 967.3 ± 545.3 U/L (79 to 2,630). There was no difference in mean BMI (P=0.1) and mean duration of operation (P=0.5) between males and females. However, a statistically significant difference in mean elevation of CPK between males and females (P=0.003) was found. The variables sex, age, weight and duration of surgery were analyzed by multivariate logistic regression, but did not show a statistically significant difference. Conclusion: Rhabdomyolysis is a potentially fatal complication of surgical procedures in obese patients, and can be minimized with simple measures such as additional padding, aggressive hydration and urine alkalinization. Diagnosis requires a high level of physician awareness. Key words: Rhabdomyolysis, morbid obesity, bariatric surgery, gastric bypass Reprint requests to: Décio Alexandre de Freitas Carvalho, Rua Piauí, 854 – apto. 402, Londrina PR, 86020 390, Brazil. Email: [email protected]

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Introduction Obese individuals are at increased risk for developing co-morbidities, including hypertension, type 2 diabetes, osteoarthritis, sleep apnea, dyslipidemia, cardiovascular disease, stroke, gallbladder disease, hyperuricemia and gout. Certain cancers are also associated with obesity, including colorectal and prostate in men and endometrial and breast in women. The U.S. Department of Health and Human Services and the World Health Organization have defined overweight as a body mass index (BMI) >25 kg/m2 and obesity as a BMI ≥30 kg/m2, with Class I obesity – BMI 30.0-34.9 kg/m2, Class II obesity – BMI 35.039.9 kg/m2 and Class III obesity – BMI ≥40 kg/m2.1 The optimal treatment for obese patients with class III and class II obesity associated with co-morbidities, is bariatric surgery. With the popularization of surgery for morbid obesity, the number of operations has markedly increased, as well as the number of postoperative complications.2 Rhabdomyolysis is an uncommon event but a potential threat. In 2003, Bostanjian et al,3 TorresVillalobos et al,4 Wiltshire and Custer,5 and in 2004, Khurana et al,6 Mognol et al7 and Delfino et al8 described cases of this early complication. The severity of this illness ranges from asymptomatic elevations of serum muscle enzyme levels to life-threatening cases associated with extreme enzyme elevation, muscle necrosis, compartment syndrome, acute renal failure, electrolyte imbalance such as hypercalemia, hypocalcemia, hyperphosphatemia, acidosis and cardiac arrest.9,10 This study investigated 98 obese patients who underwent bariatric surgery without postoperative complications, © FD-Communications Inc.

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to determine the creatinine phosphokinase (CPK) elevation pattern after these operations and to emphasize that early diagnosis and treatment are the cornerstones of successful management of rhabdomyolysis.

Materials and Methods We studied 98 consecutive obese patients who underwent primary bariatric surgery from January 2004 to June 2005. All patients operated in that period by the same medical team were included. The operation performed was the open gastric bypass of FobiCapella.11 A database was created for all patients (sex, age, BMI, duration of the operation, levels of serum CPK systematically measured before surgery and on the first and second postoperative day). The measurements of CPK were performed using a Dimension® clinical chemistry system, Flex® reagent cartridge (Dade Behring, Deerfield, IL, USA), which is an in vitro test for the quantitative determination of CPK activity in serum and heparinized plasma. The method is a modification of the UV enzymatic determination described by Oliver and Rosalki.12,13 The reference (normal) level at 37˚C ranged from 35 to 232 U/L in males and from 21 to 215 U/L in females. In the present study, we used a fivefold or greater increase in serum CPK in patients without apparent cardiac or brain injury as the only diagnostic criterion for rhabdomyolysis (males CPK ≥1,160 U/L and females CPK ≥1,075 U/L).14,15 The results are presented as mean values with standard deviation. The Student t-test was used to compare group means. Chi-square testing was used to compare the values of CPK elevation between men and women. P values <0.05 were considered significant. The protocol was approved by the Ethics in Research Committee of the Institution – State University of Londrina (UEL), Parana, Brazil.

Results The study sample consisted of 35 males (35.7%, n= 35) and 63 females (64.3%, n=64) with mean age 37.4 ± 10.7 years (range 18 to 64 years); mean BMI

43.2 ± 6.8 kg/m2 (range 34 to 82 kg/m2); mean duration of operation 3.6 ± 0.8 hours (range 2.75 to 8.0 hours); mean CPK level in the preoperative period 156.6 ± 41.1 U/L (range 40 to 220 U/L), postoperative 24 hours 1,075.2 ± 596.5 U/L (range 85 to 2,790 U/L) and postoperative 48 hours 967.3 ± 545.3 U/L (range 79 to 2,630 U/L) (Table 1). There was no difference in mean BMI (P=0.1) and mean duration of operation (P=0.5) between males and females. A statistically significant difference was found in the mean elevation of CPK levels between males and females (P=0.003). The pattern of CPK elevation after uncomplicated bariatric surgery was then determined. The variables sex, age, weight and duration of surgery were analyzed using the multivariate logistic regression model. Hosmer and Lemeshow Goodness-of-fit test was used (x2=10.2850, df=8, P-value=0.2456) indicating that the model was adequate for the data. Those variables did not present statistical differences. It is important to be aware of the OR magnitude and respective confidence intervals for sex and duration of surgery, which lead us to think that the lack of significance could be observed because the sample size was insufficient to analyze simultaneously all those variables. The highest levels of CPK were found on the first day after surgery (1,075.2 ± 596.5 U/L). On the second day after surgery, there was a slight decrease in the levels of CPK (967.3 ± 545.3 U/L) (Figure 1). Of the men, 54.3% (n=19) and of the women, 28.6% (n=18) presented CPK levels fivefold or greater than the CPK reference levels, and a diagnosis of rhabdomyolysis was given. Men were more susceptible to developing rhabdomyolysis than women (χ2=6.3307, P=0.012). Table 2 shows the Table 1. Characteristics of patients

Age (years) BMI (kg/m2) Duration of operation (hours) CPK Preop (U/L) CPK Postop 24 hours (U/L) CPK Postop 48 hours (U/L)

Mean

Standard Deviation

Range

37.4 43.2

10.7 6.8

18 - 64 34 - 82

3.6 156.6

0.8 41.1

2.75 - 8 40 - 220

1075.2

596.5

85 - 2790

967.3

545.3

79 - 2630

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9

1075.2

8

1000 967.3

7 6

Hours

CPK (U/L)

800 600 400

2

156.6

0 Preop Pré Op

1 0

PO 1d Days

PO 2d

Discussion The first modern description of rhabdomyolysis is attributed to Bywaters and Beall;16 in 1941, they described four cases of victims of crushing injuries during the bombing of London in the battle of Britain. All of them developed acute renal failure and died within 1 week.16 Table 2. Patients diagnosed as having rhabdomyolysis

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500

1000

1500

2000

2500

3000

Figure 2. Duration of operation versus CPK levels in 24 hours.

characteristics of the group of patients diagnosed as having rhabdomyolysis. The diagnosis of rhabdomyolysis in these patients was based on the biochemical determinations only, because none of them presented any other signs or symptoms of the syndrome. Five patients required an operating time >5 hours. The BMI of these patients ranged from 45 to 82 kg/m2 and the CPK levels after 24 hours ranged from 88 to 2,038 U/L (Table 3 and Figures 2 and 3). The highest level of CPK (2,790 U/L) was found in a man whose BMI was 56 kg/m2 and the duration of his surgical procedure was 4.25 hours. The highest levels of CPK were measured in patients whose BMI ranged from 42 to 56 kg/m2, but not in patients whose BMI was >60 kg/m2 (Figure 4).

Age (years) BMI (kg/m2) Duration of operation (hours) CPK Preop (U/L) CPK Postop 24 hours (U/L) CPK Postop 48 hours (U/L)

0

CPK (U/L) U/L CPK

Figure 1. Levels of CPK.

742

4 3

Mean

Range

37.8 45.1 3.9 166.8 1693.2 1518.9

21 - 64 35 - 57 3-8 41 - 216 1100 - 2790 930 - 2620

90 80 70 60 BMI (kg/m2)

200

5

50 40 30 20 10 0 0

1

2

3

4

Hours

5

6

7

8

9

Figure 3. BMI versus duration of operation.

Rhabdomyolysis is a clinical and biochemical syndrome characterized by skeletal muscle necrosis with the release of intracellular muscle contents into the circulatory system. The cell contents include enzymes such as: CPK; glutamic oxaloacetic transaminase; lactate dehydrogenase; aldolase; the heme pigment, myoglobin; electrolytes such as potassium and phosphate; and purines. CPK is the most sensitive enzyme marker of muscle injury and is readily determined in most hospital laboratories.14 In the majority of cases, the cause of rhabdomyolysis is evident in the patient’s clinical history or in Table 3. Patients who had duration of operation ≥5 hours Sex

F F M F F

BMI kg/m2

CPK U/L

Duration of operation (hours)

46 82 65 46 45

88 565 985 2018 2038

5 6 6.5 8 6.5

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Rhabdomyolysis after Bariatric Surgery 90 80

BMI (kg/m2)

70 60 50 40 30 20 10 0 0

500

1000

1500

2000

2500

3000

CPK (U/L) U/L

Figure 4. BMI versus CPK at 24 hours.

circumstances that precede its cause, such as postoperative trauma, extreme exertion and seizures.15 Occasionally, the cause of rhabdomyolysis is not obvious. Some of these cases are caused by muscular enzyme deficiency, electrolytic imbalance, infections, drugs, toxins or endocrine diseases.15 The operating-room is a favorable environment for the development of rhabdomyolysis. Long operations with the patient maintained in unusual positions are associated with increased pressure on certain body regions, which can cause necrotic injuries.17-19 Anesthesia and postoperative analgesia are believed to increase the risk of this complication, because they prevent patient movement and awareness of pain; thus, patients are unable to change body position, alternating the points which are under high pressure. This can delay the diagnosis and treatment of rhabdomyolysis.3 Individuals with increased risk for rhabdomyolysis are super-obese male patients with hypertension and/or diabetes, and prolonged duration of surgery.3 Patients with BMI ≤25 kg/m2 can also develop rhabdomyolysis, attributed to the prolonged period that they remain in certain positions (lithotomy, lateral, knee-chest position). Even in the supine position these patients can be victims of rhabdomyolysis when surgery lasts >7 hours.20,21 Diagnosis requires a high level of physician awareness. Its presence can be confirmed with a simple laboratory test. The most common signals and symptoms are: muscular pain (24%), muscular weakness (19%); proteinuria (39%) and pigmenturia (36%).22 CPK in the serum, myoglobin in the serum and urine, and electrolytes including calcium and phosphorus can be measured.23 Other tests include LDH, AST levels and imaging studies such

as CT scan and magnetic resonance.20 The initial treatment of rhabdomyolysis consists of the administration of volume, diuresis stimulation with mannitol and urine alkalinization with sodium bicarbonate to prevent myoglobin deposition in the renal tubules. These procedures are important to prevent the depletion of volume, renal tubular damage and the release of free radicals that are an important renal injury mechanism.3 Bostanjian et al3 adopted the routine of placing additional buttock padding in very obese patients, diminishing the pressure exerted on this area during surgical procedures, and they instituted aggressive hydration and mannitol when patient CPK levels were >5,000 U/L. According to these authors, the chances of complications caused by muscle necrosis when CPK levels are ≤5,000 U/L are minimal.3 Renal function can be improved when acute renal failure caused by rhabdomyolysis is promptly treated; therefore early diagnosis is extremely important. In the present study, the peak of CPK elevation occurred in 96.8% of patients on the first day after surgery. This finding differs from that of Bostanjian,3 who verified CPK peaks on the second day after surgery. A biochemical diagnosis of rhabdomyolysis was made in 28.6% of women and 54.3% of men, despite the fact that these two groups presented no significant statistical difference between surgical time and BMI. In the study sample, there were seven patients (7.3%) with BMI ≥50 kg/m2. The surgical time was relatively short (mean 3.6 hours) in all cases, but even so biochemical diagnosis of rhabdomyolysis was found in 37.8% of patients. The rise in CPK levels was greater in men than in women, but did not correlate with BMI or surgical time in this study. Other risk factors for developing this syndrome, such as associated co-morbidities, the use of cholesterol-reducing drugs, coma and congenital muscular enzyme deficiencies were not studied.

Conclusion Rhabdomyolysis is a potentially fatal complication during prolonged surgical procedures, particularly in obese patients, whose consequences can be minimized with simple measures such as additional padding, aggressive hydration and urine alkalinizaObesity Surgery, 16, 2006

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tion. As the majority of patients receive analgesia in the postoperative period, some symptoms, such as myalgia, may not be apparent, which can cause delay in diagnosis and treatment. Measuring CPK before and after bariatric surgery enables early detection of rhabdomyolysis. If there is any doubt regarding diagnosis, treatment should be instituted. Early diagnosis and treatment are crucial to attain a resolution. In the present study, a peak rise in CPK levels on the first day after surgery and a slight fall in these levels on the second day after surgery were observed. CPK is an inexpensive, easily-done test, which we draw routinely pre- and postoperatively on all patients undergoing bariatric surgery. We treat all patients with CPK >1000 with further hydration until urine output of 100 ml/hr is achieved, despite no physical findings.

References 1. Khaodhiar L, McCowen KC, Blackburn GL. Obesity and its comorbid conditions. Clin Cornerstone 1999; 2: 17-31. 2. Printen KJ, Paulk SC, Mason EE. Acute postoperative wound complications after gastric surgery for morbid obesity. Am Surg 1975; 41: 483-5. 3. Bostanjian D, Anthone GJ, Hamoui N et al. Rhabdomyolysis of gluteal muscles leading to renal failure: a potentially fatal complication of surgery in the morbidly obese. Obes Surg 2003; 13: 302-5. 4. Torres-Villalobos G, Kimura E, Mosqueda JL et al. Pressure-induced rhabdomyolysis after bariatric surgery. Obes Surg 2003; 13: 297-301. 5. Wiltshire JP, Custer T. Lumbar muscle rhabdomyolysis as a cause of acute renal failure after Roux-en-Y gastric bypass. Obes Surg 2003; 13: 306-13. 6. Khurana RN, Baudendistel TE, Morgan EF et al. Postoperative rhabdomyolysis following laparoscopic gastric bypass in the morbidly obese. Arch Surg 2004; 139: 73-6. 7. Mognol P, Vignes S, Chosidow D et al. Rhabdomyolysis after laparoscopic bariatric surgery. Obes Surg 2004; 14: 91-4. 8. Delfino V. IRA por rabdomiólise após cirurgia bar-

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iátrica. JBN 2004; 26: 145-8. 9. Prince RL, Hutchison BG, Bhagat CI. Hypercalcemia during resolution of acute renal failure associated with rhabdomyolysis: evidence for suppression of parathyroid hormone and calcitriol. Aust NZ J Med 1986; 16: 506-8. 10.Bogaerts Y, Lameire N, Ringoir S. The compartmental syndrome: a serious complication of acute rhabdomyolysis. Clin Nephrol 1982; 17: 206-11. 11.Fobi MA, Lee H, Felahy B et al. Choosing an operation for weight control, and the transected banded gastric bypass. Obes Surg 2005; 15: 114-21. 12.Oliver IT. A spectrophotometric method for the determination of creatine phosphokinase and myokinase. Biochem J 1955; 61: 116-22. 13.Rosalki SB. An improved procedure for serum creatine phosphokinase determination. J Lab Clin Med 1967; 69: 696-705. 14.Gabow PA, Kaehny WD, Kelleher SP. The spectrum of rhabdomyolysis. Medicine (Baltimore) 1982; 61: 141-52. 15.Warren JD, Blumbergs PC, Thompson PD. Rhabdomyolysis: a review. Muscle Nerve 2002; 25: 332-47. 16.Bywaters EG, Beall D. Crush injuries with impairment of renal function. 1941. J Am Soc Nephrol 1998; 9: 322-32. 17.Ettinger JEMTM, Filho PVS, Azaro E et al. Prevention of rhabomyolysis in bariatric surgery. Obes Surg 2005; 15: 874-9. 18.Stroh C, Hohmann U, Remmler K et al. Rhabdomyolysis after biliopancreatic diversion with duodenal switch. Obes Surg 2005; 15: 1347-51. 19.Filis D, Daskalokis M, Askoxylakis I et al. Rhabdomyolysis following laparoscopic gastric bypass. Obes Surg 2005; 15: 1496-500. 20.Knochel JP. Rhabdomyolysis and myoglobinuria. Annu Rev Med 1982; 33: 435-43. 21.Biswas S, Gnanasekaran I, Ivatury RR et al. Exaggerated lithotomy position-related rhabdomyolysis. Am Surg 1997; 63: 361-4. 22.Pascual JM, Gorriz JL, Prosper M et al. [Acute rhabdomyolysis. A study of 44 cases]. Rev Clin Esp 1990; 187: 6-9. 23.Allison RC, Bedsole DL. The other medical causes of rhabdomyolysis. Am J Med Sci 2003; 326: 79-88. (Received December 28, 2005; accepted February 17, 2006)