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Safety and effectiveness of the combination acetazolamide and bicarbonates to induce alkaline diuresis in patients with rhabdomyolysis
  1. Konstantinos Ioannidis1,
  2. Apostolos Papachristos1,
  3. Zoe Athanassa2,
  4. Emmanouela Katsouda2,
  5. Ioannis Skarlatinis1,
  6. Haris Paskalis2
  1. 1Department of Pharmacy, Hygeia Hospital Athens, Athens, Greece
  2. 2Intensive Care Unit, Hygeia Hospital Athens, Athens, Greece
  1. Correspondence to Dr Konstantinos Ioannidis, Department of Pharmacy, Hygeia Hospital Athens, Erythrou Stavrou 4 & Kifisias, Marousi, Athens 15123, Greece; kioannidis{at}hygeia.gr

Abstract

Objectives The therapeutic goal in rhabdomyolysis includes treatment of the causative factor and symptoms, and prevention of complications. Administration of intravenous fluids and forced alkaline diuresis are essential. Both intravenous bicarbonates and acetazolamide are used to increase urine pH but have limitations and are associated with an increased risk of metabolic abnormalities. The purpose of this study is to evaluate the effectiveness and safety of the concurrent use of acetazolamide and bicarbonates in order to achieve urine alkalisation and avoid metabolic abnormalities.

Methods We conducted a retrospective study of the medical records of patients with rhabdomyolysis who received intravenous acetazolamide and sodium bicarbonate.

Results 12 patients (9 males and 3 females) with median age of 47.5 years were analysed. All had creatinine clearance >10 mL/min. The median maximum creatine phosphokinase (CPK) was 14 280 IU/L, and the median duration of treatment in order to achieve CPK levels <5000 IU/L was 3 days. Median urine and blood pH levels were within normal ranges at 7.75 and 7.4, respectively. Median electrolyte values were: potassium 3.6 mmol/L, ionised calcium in plasma 1.1 mmol/L, and bicarbonates 25.6 meq/L. The median creatinine clearance was 43.5 mL/min. No patient required chronic haemodialysis.

Conclusions In the present study, the combined use of acetazolamide and bicarbonates was effective and safe as we achieved alkaline urines on the first day and CPK levels were reduced to <5000 IU/L within 3 days, no patient needed chronic haemodialysis, and no electrolyte or metabolic abnormalities were observed.

  • CLINICAL PHARMACY
  • CLINICAL PHARMACOLOGY
  • GENERAL MEDICINE (see Internal Medicine)
  • PHARMACOTHERAPY
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Introduction

Rhabdomyolysis is characterised by muscle necrosis and the release of intracellular muscle constituents into the circulation. Electrolyte disturbances, markedly elevated levels of creatine phosphokinase (CPK) and myoglobin in body fluids, muscle pain and myoglobinuria are typically present. The severity of illness ranges from asymptomatic elevations in serum muscle enzymes to life-threatening disease associated with extreme enzyme elevation, electrolyte imbalance and acute kidney injury (AKI).1 ,2 The causes of rhabdomyolysis can be divided into traumatic, non-traumatic exertional and non-traumatic non-exertional.3 ,4 ,5

Muscle pain, weakness and dark urine are the most characteristic symptoms; however, approximately 50% of patients may not report muscular symptoms, while others experience very severe pain. Moreover, other common symptoms are malaise, fever, tachycardia, nausea, vomiting and abdominal pain.3 ,6 ,7 The most typical laboratory finding in rhabdomyolysis is an elevation in CPK level. It begins to rise 2–12 h after the onset of muscle injury with peak levels reached within 3 days. As CPK has a serum half-life of about 1.5 days, levels decline daily by about 40–50% of the previous day's value.3 ,8 ,9 Another typical finding is the reddish-brown urine of myoglobinuria. Visible changes in the urine only occur when myoglobulin urine levels exceed 100–300 mg/dL. However, as urine dipstick can detect myoglobulin at concentrations of only 0.5–1 mg/dL, myoglobinuria is observed in only half of the patients who have it.4 The most important complication following rhabdomyolysis is AKI. Its frequency ranges from 15% to 50% and is increased in patients with CPK levels at admission of more than 5000–20 000 IU/L. Other risk factors for AKI include dehydration, sepsis and acidosis.2 ,4 ,5 ,10

The therapeutic goal in rhabdomyolysis is to treat the underlying cause and to prevent haem pigment-induced AKI. Two commonly used approaches to prevent AKI are correction of volume depletion by administering intravenous fluids and prevention of intratubular cast formation by administering bicarbonates to force alkaline diuresis. Despite the fact that the administration of bicarbonates is standard clinical practice,1 the benefits of their use are controversial in the literature. Two main issues are reported concerning treatment with bicarbonates: the difficulty of maintaining the urine pH above 6.5 in patients with AKI and adverse events such as alkalosis, severe hypokalaemia and hypocalcaemia.6

Thus, we hypothesised that concurrent administration of acetazolamide with bicarbonates could achieve urine alkalisation, and prevent alkalosis or acidosis and significant electrolyte abnormalities. The purpose of the present study was to assess the effectiveness and safety of this combination therapy in patients with rhabdomyolysis who were admitted to intensive care.

Methods

We conducted a retrospective study of the medical records of patients with rhabdomyolysis admitted to the intensive care unit of a tertiary hospital from January 2011 to December 2013. The hospital information system was used to identify patients. Patients were included in our study if they were over 18 years of age, had an admission diagnosis possibly causing rhabdomyolysis (eg, trauma, arterial occlusion) confirmed with a discharge ICD-10 code, baseline CPK values above 5000 IU/L, creatinine clearance above 10 mL/min calculated with 24 h urine measurement, and treatment for rhabdomyolysis with concurrent administration of acetazolamide and bicarbonates. Patients were excluded from our study if they had baseline CPK values below 5000 IU/L, creatinine clearance values below 10 mL/min calculated with 24 h urine measurement, were receiving renal replacement therapy, had severe congestive heart failure precluding aggressive fluid resuscitation, and already had AKI with anuria.

All patients received adequate fluid resuscitation with isotonic saline or lactated Ringer's solution at initial infusion rates ranging from 400 to 800 mL/h depending on the type of condition and severity of rhabdomyolysis; the infusion rate was then titrated to maintain urine output of at least 200 mL/h.2 Furthermore, all patients received appropriate medication therapy as indicated for their admission diagnosis. In addition, patients received intravenous acetazolamide 500 mg every 8 h if creatinine clearance was above 50 mL/min or every 12 h if creatinine clearance was 10–50 mL/min. Sodium bicarbonate solution 8.4% w/v was administered intravenously at a continuous rate of 10 mL/h. The study protocol was approved by the scientific and ethics committee of our hospital and anonymity was guaranteed. A total of 36 patients were screened.

For each patient the following data were recorded: age, sex, weight, height, cause of rhabdomyolysis, CPK, urine and blood pH, positive urine dipstick haemoglobulin reaction, creatinine (Cr), creatinine clearance (CrCl) and electrolytes. The data were analysed with descriptive statistics.

Results

Review of the records of 36 patients revealed 12 (9 male and 3 female) who met the eligibility criteria and were included in our analysis. The remaining patients were excluded due to baseline CPK values below 5000 IU/L (6 patients, who did not receive the combination) and lack of data concerning urine pH (5 patients), blood pH (6 patients) and CPK values on day 3 of treatment (7 patients) (figure 1). The demographic and clinical data of the eligible patients and the outcomes of this study are shown in table 1. The median age of the study population was 47.5 (19–76) years. All patients had a positive urine dipstick haemoglobulin reaction (+3) at admission. The causes of rhabdomyolysis were non-traumatic in eight (66.7%) and traumatic in four (33.3%) patients. The median length of treatment was 4.4 (2–10) days and the median length of stay was 29.8 (8–92) days (table 1). Alkalisation of urine was achieved in all patients within the first 4 h of treatment with median urine pH values of 7.75 (7.25–8.5) while at the same time blood pH remained within normal levels with a median pH value of 7.4 (7.3–7.43) (table 2). CPK levels decreased below 5000 IU/L by a median of 3 (1–5) days (table 3). In addition, no electrolyte or metabolic abnormalities were observed (table 3).

Table 1

Demographic and clinical data

Table 2

Blood/urine pH and creatinine clearance (CrCl; mL/min) over treatment period

Table 3

Creatine phosphokinase (CPK; IU/L), HCO3 (mmol/L) and K+ (mmol/L) values over treatment period

Figure 1

Patient flow chart. CPK, creatine phosphokinase; CrCl, creatinine clearance.

Moreover, median creatinine clearance values were 48.2 (10–100) mL/min at baseline, and 51.7 (12–105) mL/min at the end of treatment (figure 2 and table 2). In addition, no patient needed haemodialysis during the study period or during a follow-up period of 3 months.

Figure 2

Creatinine clearance (CrCl) at baseline and at the end of treatment.

Discussion

Treatment strategies for rhabdomyolysis include reversal of cause, treatment of associated clinical symptoms and laboratory abnormalities, and prevention of further complications such as AKI.

AKI is caused by the non-protein haem pigment that is released from myoglobin and is toxic to the kidney.2 ,4 ,5 ,10

The first step is the administration of intravenous fluids in order to avoid rhabdomyolysis-induced AKI. The goal is to maintain or enhance renal perfusion, thereby minimising ischaemic injury, and to increase the urine flow rate thereby limiting intratubular cast formation. Loop diuretics and/or mannitol can be used for diuresis, but their use in rhabdomyolysis is not well established.9 ,11 ,12 Experimental studies suggested that mannitol might be protective by increasing diuresis, which minimises intratubular haem pigment deposition and cast formation, and/or by acting as a free radical scavenger, thereby minimising cell injury.11 ,12 However, mannitol did not ameliorate proximal tubular necrosis, suggesting that induced diuresis was its most important effect.12 In addition, loop diuretics have no impact on outcome in AKI, because they can worsen the pre-existing trend for hypocalcaemia, since they induce calciuria and may increase the risk of cast formation.13–16

Treatment of rhabdomyolysis with bicarbonates is controversial due to uncertainty about their efficacy and severe adverse events. However, their use is considered to be standard clinical practice.1 They force alkaline diuresis by raising the urine pH above 6.5. Urine alkalisation prevents haem protein precipitation with Tamm-Horsfall protein, and therefore intratubular pigment cast formation. Additionally, it decreases the release of free iron from myoglobin and the formation of F2-isoprostanes, which may enhance renal vasoconstriction and decrease the risk of tubular precipitation of uric acid.1 ,4 ,17 In spite of the above advantages, maintaining urine pH above 6.5 is difficult in patients with AKI and the use of bicarbonates also presents significant limitations. Bicarbonates can be used when severe hypocalcaemia is absent, arterial pH is below 7.50 and serum bicarbonate is less than 30 meq/L. Other risks include the promotion of calcium phosphate deposition, especially when hypophosphataemia is present, and inducing or worsening the manifestations of hypocalcaemia.8 Manifestations of severe hypocalcaemia include tetany, seizures and cardiac arrhythmias that increase mortality in critical ill patients. When bicarbonates are given, arterial pH and serum calcium should be monitored every 2 h during the infusion and if urine pH does not rise above 6.5 after 3–4 h, the bicarbonate infusion should be discontinued. It must also be discontinued if the patient develops symptomatic hypocalcaemia, alkalosis or if the serum bicarbonate exceeds 30 meq/L. If administration is successful and diuresis is established, therapy should continue until plasma CPK decreases to less than 5000 U/L.

Another possible option to prevent AKI due to rhabdomyolysis is the administration of acetazolamide, which is a diuretic that causes reversible inhibition of carbonic anhydrase, and as a result reduces hydrogen ion secretion in renal tubules, and increases renal excretion of sodium, potassium, bicarbonate and water thereby inducing alkaline diuresis.18 Although acetazolamide can be considered as an effective diuretic and a good therapeutic option in patients with rhabdomyolysis, it also presents some significant limitations with the most important being the increased risk of metabolic acidosis. Finally, acetazolamide cannot be used in patients with creatinine clearance below 10 mL/min, mainly because lack of efficacy in such patients.18–20

In this study we examined the safety and the efficacy of combination therapy with bicarbonates and acetazolamide in achieving urine alkalisation in patients with rhabdomyolysis. This combination has been studied in patients with cancer and is recommended for urine alkalisation before the administration of high-dose methotrexate.21 Bicarbonate and acetazolamide administered intravenously appear to act synergistically in maintaining urine pH above 6.5 by the mechanism shown in figure 3. However, the main benefit of the combination is to eliminate the adverse effects observed when each drug is given separately for rhabdomyolysis. The results of this study showed that, in all patients, urine alkalisation was achieved within 4 h of initiation of bicarbonate and acetazolamide administration. However, in previous reports describing monotherapy with bicarbonates, achievement of urine pH above 6.5 was delayed or not achieved at all in patients with rhabdomyolysis.18–20 In addition, monotherapy with acetazolamide has been associated with acidosis.18–20 The limited evidence of this study suggests that combination therapy with bicarbonates and acetazolamide may be safe since none of our patients showed metabolic or electrolyte disturbances requiring treatment termination.8 ,18 In addition, no patient needed haemodialysis during a follow-up period of 3 months, which may be explained by the quick decline in blood CPK levels to below 5000 IU/L (within 3 days), which is related to the development of kidney injury in patients with rhabdomyolysis.1 ,4 ,17

Figure 3

Mechanism of action of the concurrent use of acetazolamide and bicarbonates. Acetazolamide inhibits carbonic anhydrase and so inhibits reabsorption of bicarbonates and as a result increases urine pH. At the same time bicarbonates were infused to keep blood pH stable.

To our knowledge this is the first study to examine the effect of the concurrent use of acetazolamide and bicarbonates in the treatment of rhabdomyolysis. As already mentioned, our goal was to achieve rapid urine alkalisation and CPK reduction. This combination therapy might be a treatment option as our results have shown that it is effective for urine alkalisation from the first day of treatment and reduces CPK levels to below 5000 IU/L by the third day of treatment. In addition, no patient required chronic haemodialysis and no electrolyte or metabolic abnormalities were observed. However, the present study has some limitations as it is an observational, retrospective, non-randomised study in a small number of patients. Therefore, further investigations such as larger prospective and comparative studies between combination and monotherapy with bicarbonates or acetazolamide, should be performed to ensure effectiveness and safety and clarify if the concurrent use of acetazolamide and bicarbonates is a feasible approach for the treatment of patients with rhabdomyolysis (figure 4).

Key messages

  • What is already known on this subject

  • Acute kidney injury is a major complication in patients with rhabdomyolysis.

  • In order to avoid acute kidney injury, alkalisation of urine is required and should be achieved as soon as possible in patients with creatine phosphokinase (CPK) >5000 IU/L; bicarbonates are widely used in clinical practice to induce alkaline diuresis.

  • The efficacy of bicarbonates for the alkalisation of urines is controversial and their use is associated with metabolic abnormalities and alkalosis.

  • What this study adds

  • A new combination treatment of acetazolimide and bicarbonates takes advantage of the mechanism of action of both agents and provides a better safety profile as the metabolic and electrolyte abnormalities associated with bicarbonate use are avoided.

  • The combination offers fast alkalisation of urine and protects the patient from acute kidney injury.

Figure 4

Therapeutic algorithm. CPK, creatine phosphokinase.

References

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Footnotes

  • Contributors KI, HP: study conception and design; IS, AP: acquisition of data; KI, AP: analysis and interpretation of data; KI, AP, ZA, EK: drafting of the manuscript: HP: critical revision of the manuscript.

  • Competing interests None.

  • Ethics approval The Scientific and Ethics Committee of Hygeia Hospital approved this study.

  • Provenance and peer review Not commissioned; internally peer reviewed.

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