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Original Article

Muscle enzyme elevation after elective neurosurgery

Poli, D.*; Gemma, M.*; Cozzi, S.*; Lugani, D.*; Germagnoli, L.; Beretta, L.*

Author Information
European Journal of Anaesthesiology: June 2007 - Volume 24 - Issue 6 - p 551-555
doi: 10.1017/S0265021506002389



Rhabdomyolysis is a clinical syndrome characterized by the destruction of muscle tissue and by the subsequent release from damaged muscle cells of a large number of intracellular components, such as myoglobin, potassium, cytokines [1], free oxygen radicals [2], histamine and platelet-activating factor [3], which have toxic effects on adjacent and distant structures. The magnitude of these toxic effects varies greatly depending on the damaged muscle tissue mass and on the pre-existing conditions of the patient [4-9]. It ranges from asymptomatic forms, revealed only by high blood levels of typical biochemical markers, to catastrophic syndromes leading to renal failure, severe hyperkalaemia, shock, acute respiratory distress syndrome and death [10].

It is well known how individual susceptibility to drugs can lead to rhabdomyolysis or even malignant hyperthermia during anaesthesia. A high level of suspicion is needed to promptly diagnose these severe conditions, since fortunately they are uncommon [11-13]. On the other hand, direct muscle damage occurs frequently during surgery since muscle section or retraction is needed for accessing the surgical field [14]. Some cases of muscular damage occurring during anaesthesia have also been reported as compartment syndrome related to the loss of muscle tone and prolonged immobility during surgery, especially when associated with incorrect positioning. In some respects, this syndrome resembles the rhabdomyolysis of crush syndrome [15,16] and of prolonged coma. Such a ‘positional' rhabdomyolysis has been reported in series and case reports, mostly regarding bariatric, urologic and gynaecologic surgery [17,18].

To our knowledge, the incidence, risk factors and clinical impact of positional rhabdomyolysis during neurosurgery have not been reported. Given the small amount of muscle involved, it is conceivable that direct surgical muscle damage plays a negligible role in neurosurgery. On the other hand, we have occasionally noticed elevated postoperative creatine kinase (CK) after intracranial neurosurgery in our clinical practice. To assess whether the issue of postoperative muscle enzyme elevation is relevant to neurosurgery, we prospectively measured serum CK and myoglobin (MG) in a series of neurosurgical patients submitted to craniotomy.

Materials and methods

The study received the approval of the local Ethics Committee of our Hospital. Thirty consecutive ASA I–II patients scheduled to undergo craniotomy for elective supratentorial neurosurgery in the supine position lasting longer than 3 h entered the study after signing informed consent. We explicitly excluded patients younger than 18 yr or older than 70 yr, patients with personal or family evidence or history of myopathy, nephropathy, malignant hyperthermia or rhabdomyolysis (after anaesthesia, heat or any other precipitating factor), and patients to whom depolarizing relaxing agents had to be administered because difficult intubation was foreseen. Patients presenting abnormal preoperative serum CK, MG, lactate dehydrogenase (LDH), aspartate aminotransferase (AST), alanine aminotransferase (ALT), blood urea nitrogen (BUN), creatinine, Na+, K+ and Ca2+ were also excluded. Five patients were excluded after enrollment because during the study period they exhibited seizures (three patients) or were transfused with a volume of packed red blood cells greater than 30% estimated blood volume (66 mL kg−1 for males and 60 mL kg−1 for females) (two patients). A total of 25 patients were actually studied. Patients with a history of statin use, alcohol or drug abuse or tobacco addiction were also excluded.

All of the patients received diazepam 0.125 mg kg−1 orally and atropine 0.5 mg intramuscularly (i.m.) 1 h before induction of anaesthesia. Anaesthesia was induced with fentanyl 0.1 mg intravenously (i.v.) followed by thiopental 5 mg kg−1 i.v. and cisatracurium 0.15 mg kg−1 i.v. After orotracheal intubation, mechanical ventilation was adjusted in order to maintain PaCO2 = 30–35 mmHg and FiO2 = 0.4 throughout surgery. Anaesthesia was maintained with i.v. propofol 4–5 mg kg−1 h−1. A continuous infusion of remifentanil was titrated to provide analgesia throughout surgery. No i.m. drug injection was administered postoperatively.

Radial invasive mean arterial pressure (MAP), 3-lead electrocardiogram, oxygen saturation, FiO2, end-tidal carbon dioxide, diuresis and rectal temperature were continuously monitored. MAP values were recorded every 5 min. We also recorded age, gender, body mass index (BMI), lowest rectal temperature reached during surgery and time elapsed from induction of anaesthesia to extubation (time of surgery).

Peripheral venous blood samples were drawn immediately after induction of anaesthesia (T0), at the end of surgery (Te), after 24 h (T1), 48 h (T2) and 72 h (T3) for measuring serum CK, MG, AST, ALT, LDH, BUN, Creatinine, Na+, K+ and Ca2+.

Statistical methods

Statistical analysis was performed using Systat v. 11.0TM (Systat Corp., Inc.). Continuous variables are expressed as median (interquartile range) and were compared with the Wilcoxon signed rank sum test. Model estimation was performed using backward stepwise logistic regression analysis with alpha-to-enter and alpha-to-exit 0.15, after appropriate ranking. Comparisons were considered statistically significant when P < 0.05.


Serum LDH, BUN, creatinine, Na+, K+ and Ca2+ did not differ significantly in any patient at any time point. In two patients, serum AST were elevated at T1 (128 and 173 IU L−1) but they substantially lowered during the following days. The same patients exhibited a serum ALT rise at T2 (90 and 108 IU L−1, respectively), which also reduced at T3. All the patients had a urine output ≥24 mL kg−1 day−1 during the study period. No postoperative infection was recorded during the study period.

CK (normal values 20–170 UI L−1) was not significantly elevated from T0 (59 (42–94) UI L−1) at Te (67 (59–131) UI L−1). On the first day after surgery (T1), CK peaked significantly from the previous values (305 (107–1306) UI L−1; P < 0.001), then showed a progressive decrease at T2 (269 (88–947) UI L−1) and T3 (213 (77–653) UI L−1) (Fig. 1). This reduction of serum CK from the T1 peak value at T2 and T3 was significant (P < 0.005).

Figure 1.
Figure 1.:
Time course of serum creatine kinase (CK). Medians and interquartile range are represented.

MG (normal values 10–92 ng mL−1) showed different serum kinetics (Fig. 2). It differed from basal (T0) levels (36 (30–44) ng mL−1) at Te (70 (42–147) ng mL−1; P = 0.002), then remained stable at T1 (104 (37–297) ng mL−1; P = 0.363) and progressively decreased at T2 (46 (35–93) ng mL−1), eventually reaching near-normal levels on the third day after surgery (T3: 28 (22–56) ng mL−1) (P < 0.001).

Figure 2.
Figure 2.:
Time course of serum myoglobin (MG). Medians and interquartile range are represented.

To identify the elements that best describe the occurrence of rhabdomyolysis in our series, we performed backward stepwise logistic regression analysis, choosing T1 CK concentration and Te MG concentration as dependent variables. We included in the model testing as possibly related to rhabdomyolysis BMI, duration of surgery, MAP, age, lowest temperature reached during surgery, baseline CK and baseline MG levels. Duration of surgery (315 (267–445) min) was the only factor significantly correlated with peak CK (P < 0.001; R2 0.7) and MG (P = 0.011; R2 0.41) concentration.


We report a series of patients undergoing elective supratentorial neurosurgery who exhibited significant serum CK and MG elevation after surgery. However, none of our patients suffered any clinical signs of rhabdomyolysis. When dealing with rhabdomyolysis, one has to remember that it does not represent an ‘all-or-nothing' event. Its clinical spectrum is a continuum ranging from isolated elevated serum CK and MG level (as in our series) to devastating acute renal and hepatic failure, acute respiratory distress syndrome, serum electrolytes and acid–base derangement.

Serum CK is a high sensitivity marker of muscle damage: elevated CK values after trivial muscular exercise or i.m. injections are well known. It is less clear when CK values become clinically significant and relate to biological rhabdomyolysis, since different values have been proposed in the scientific literature. A reasonable approach [10,19] assumes a fivefold increase of the laboratory upper limit for normal CK as potentially clinically significant. Serum MG, on the other hand, has been mostly studied as a marker of the severity of rhabdomyolysis associated with renal failure, and not as a marker of rhabdomyolysisper se'. There is no specific value of MG beyond which renal failure ensues.

Since both markers of muscle damage rose in our series, it is conceivable that muscle impairment, even if devoid of clinical consequences, actually ensues during major, prolonged surgical procedures, irrespective of direct surgical muscle manipulation or section. The time course of the serum levels of CK and MG in our series is consistent with the known kinetic properties of the molecules [20]. MG concentration rises soon after muscle cell damage, and it is the earliest marker of muscle necrosis. CK, in contrast, rises somewhat later. In our study, MG rises early, achieving a statistically significant difference from baseline as early as at the end of surgery, while CK rises more slowly and peaks on the first postoperative day.

A number of methodological issues require comment. The preoperative i.m. atropine injection that was administered to of our patients is probably only a modest contributor to the limited direct muscle trauma. The muscular isomer CK-MM is increased after muscle injury while brain manipulation is known to increase the CK-BB sub-type of CK. Nevertheless, we measured only the total serum CK, which is commonly tested in clinical practice, and evaluated serum MG to assess the possible muscular involvement and its severity. Since common clinical practice indicates that post-traumatic muscle enzyme elevation falls rapidly, we decided to limit the study period to the third postoperative day. Our data demonstrate a significant decrease of serum CK and MB from the peak values towards normal values on the second and third day after surgery. We only studied patients operated in the supine position but it is possible that other positions would result in different amounts of CK and MG release [21,22].

Although the limited number of patients we studied does not allow a thorough examination of the risk factors for CK and MG elevation, BMI, MAP, age, body temperature, basal CK and MG levels were not correlated with the phenomenon, while duration of surgery did. During surgery, patients are unconscious, they do not move and their muscle tone is pharmacologically impaired. In this situation, the patients' body would lie for several hours over the same pressure points submitting the underlying muscles to prominent physical compression. Blood vessels are subject to compression too, and the potentially reduced tissue perfusion pressure can favour muscle ischaemic necrosis. Experimental [23-27] studies indicate 4–6 h as the critical time after which muscular ischaemia leads to irreversible tissue damage and the non-reperfusion phenomenon. The same 4–6 h time span is reported by clinical work [14,15] to be a cut-off beyond which rhabdomyolysis occurs more frequently. Our inclusion criteria with duration of surgery longer than 3 h may be a bias when length of surgery is studied as a risk factor. However, we could not exclude any case because the duration of surgery would exceed 3 h and most craniotomies last more than 3 h. It is noteworthy that most patients lying in intensive care beds for days do not develop muscle enzyme elevation even if sedated and pharmacologically paralysed. A possible explanation for this difference between the operative theatre and the intensive care unit may be the use of specialized mattresses in intensive care, which significantly reduce the pressure on muscles.

Our series indicates that a potentially significant rise in CK and MG may ensue in patients undergoing elective craniotomy in the supine position. Since this kind of surgery does not provide prominent direct muscular damage, these patients presumably suffer a kind of ‘positional' rhabdomyolysis. Fortunately, this did not lead to renal impairment in our patients, as reflected by the normal BUN, Creatinine and urine output during the study. Postoperative renal function is sometimes jeopardized in neurosurgical patients by deliberate dehydration by fluid restriction or mannitol use. In these cases, muscle damage could add to the risk of renal impairment.

In conclusion, we have demonstrated that CK and MG elevation may occur after intracranial neurosurgery. In our series, length of surgery was a risk factor and we speculate that this may reflect positional rhabdomyolysis.


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