Aprotinin in Spine Surgery: Review of the Literature

ABSTRACT

Based on a literature review, this article evaluates the efficacy of aprotinin to limit blood transfusion during spine surgery. Most prospective studies confirm this effect. However, broader studies are required to evaluate adverse effects. Severe complications are rarely, if ever, reported. Given the small size of most samples, complications are expected because of the widespread use of the drug. The cost of the medication has to be balanced with the cost of blood transfusion. A careful use of aprotinin allows a surgeon dealing with high-risk patients to avoid or limit the use of transfusions. For patients who are not high-risk, aprotinin should be avoided until other questions are answered.

Preventing Blood Loss

Blood loss in spine surgery is a constant factor of concern because of the magnitude of the operating field and the duration of the exposure, especially in cases of spinal deformity. Multiple factors contribute to the amount of blood lost during and after the procedure. Therefore, it is the surgical team’s responsibility to harness the multiple tools available to prevent blood loss.

A patient should be assessed preoperatively for pre-existing anemia or coagulopathy, which should be fully investigated and treated. Preoperative donation is used to avoid homologous blood transfusion. However, the disadvantages counterbalance the advantages: the preoperative donation technique may not prevent all transfusion errors (human errors in the manipulation and marking of the units), the cost is high, and the result is often a significant depression of the patient’s preoperative hematocrit with an increased need for transfusion during the procedure. Preoperative enhancement of the hematocrit using erythropoietin has proved to be an efficient means of increasing the amount of blood collected without exposing the patient to a deleterious iatrogenic anemia.

The anesthetic technique is an important factor in the success of blood conservation. Controlled hypotension is the most popular way of reducing blood loss during spine surgery. The risk is mainly hypoxia of end organs such as the kidney (ie, monitoring of urine output) and the spinal cord (ie, spinal cord monitoring including somatosensory evoked potentials and motor evoked potentials). Cases of blindness have been described after posterior fusions. Positioning, direct pressure on the eyes, and hypoperfusion due to hypotension have been incriminated without an effective way to monitor or prevent these complications efficiently. Normovolemic hemodilution is another way of limiting the amount of hemoglobin waste. Concerns of sufficient end organ perfusion are also risks of combining this technique with hypotension.

Proper positioning of a patient cannot be overemphasized. Pressure on the abdomen should be avoided by judicious placement of the bolsters. The Relton-Hall frame and the Jackson table are helpful for this purpose, because movable bolsters placed on a regular table can easily be displaced during the multiple correction maneuvers. A reasonable medium must be found between the procedure duration and the amount of blood loss. A careful and meticulous dissection is paramount in avoiding blood loss. However, this will prolong the procedure, which has been shown to increase blood loss. The experience of the surgeon and the team is a key factor in solving this quandary. Efficiency and systematic cauterization are the most accepted techniques. In some cases, a sequential approach (eg, lumbar then thoracic) can be performed. Our experience of 22 Jehovah’s Witness patients presenting with spinal deformities led us to specific caution and precautions to prevent avoidable bleeding. In one case, we interrupted the procedure because of the duration and significant blood loss. The patient was brought back to the operating room 2 weeks later after a correction of his hematocrit.

Pharmacological agents that control blood loss during spine surgery have been tested. Use of pharmacological agents should not be an excuse to neglect the surgical precautions mentioned earlier. Two agents are frequently studied — aprotinin and epsilon aminocaproic acid. Few studies are available to evaluate the efficiency and safety of aprotinin in spine surgery. The questions are whether aprotinin reduces the intraoperative and or postoperative blood loss, and whether it reduces the need for blood product. The appropriate dose must be determined because contradictory recommendations have been published. The initial recommended dose regimen was an initial bolus dose of 2 million units followed by continuous infusion at the rate of 0.5 million units per hour. The anticipated adverse effects are the risk of allergy in case of re-exposure (bovine-derived drug), and the hypothetical risk of thromboembolism. The cost of treatment has to be evaluated and counterbalanced with the advantages.

Studies

Lentschener et al¹ published a prospective, randomized, placebo-controlled study on 72 adult patients undergoing posterior lumbar fusion with posterior lumbar interbody fusion. In the treated group, the patients received a loading dose of 2 million units aprotinin followed by one half million units every hour until skin closure. Another bolus (0.5 million IU) was administered for every 3 packs of red blood cells transfused. Aprotinin treatment resulted in a significant decrease in the total perioperative and the first 24 hours postoperative blood loss compared with placebo-treated controls. Intraoperative blood loss was not different between the two groups. Transfusion of homologous units of blood was not significantly decreased when compared with the control group. No adverse effects were detected. However, no patient had previous exposure to the drug, and no objective test to detect clinical deep vein thrombosis had been used.

Urban et al² published a prospective randomized study on adult patients undergoing complex anterior and posterior reconstruction and fusion. This study compared a group of patients who received aprotinin at a half-dose regimen (load: 1 million units then 0.25 million units/h), a group treated with epsilon aminocaproic acid, and another group of untreated controls. The investigator does not mention when the administration of aprotinin stopped. Fifty-five patients were studied. The trigger hemoglobin level was 8 mg/L. Blood loss was significantly decreased in the aprotinin group compared with the control group (P<.01), in both total blood loss and postoperative blood loss. In the group treated with epsilon aminocaproic acid, the difference did not reach statistical significance. Similarly, transfusion requirements were significantly decreased in the aprotinin group compared with the control group (P<.05). No renal or thromboembolic complication occurred. No allergic reaction was observed.

Karapurkar et al³ conducted a prospective study on adolescent and young adult patients with scoliosis treated by posterior fusion alone. Forty-nine patients were part of the study divided into an aprotinin and a control group. The etiology of the deformity, the magnitude of the curves, and the extent of the fusion are not specified. The dose used was weight-dependent (20,000 IU/kg loading dose followed by 5,000 IU/kg/4 hours). The results were convincing because total blood loss (P<.05), intraoperative blood loss (P<.05), and blood transfusions (P<.01) were significantly improved in patients treated with aprotinin compared with controls. Also, the use of aprotinin significantly improved the surgical field as assessed by the blinded surgeon.

In a prospective, randomized, double-blind study, Cole et al⁴ compared children with spinal deformities and at high risk for massive surgical blood loss with a low-risk group of patients with regular idiopathic scoliosis. The results showed no difference in the low-risk group compared with the placebo group. Conversely, in the high-risk group (44 patients) there was a significant difference between aprotinin treatment and the controls in blood loss (P<.05) and transfusions (P<.05), while the ending hematocrit was the same in both groups (29.1 versus 29.4). The study suggests that aprotinin is effective in reducing blood loss and transfusions in high-risk patients, such as revision cases and patients with neuromuscular spinal deformities.

Summary

Blood saving is a crucial aspect of complex spine deformities. Well-accepted techniques for reduction of blood loss should be carefully respected. Careful positioning, appropriate and reasonable controlled hypotension, and meticulous surgical technique should not be neglected. However, in extreme cases or in the case of a particularly fragile patient, blood saving drugs may offer a new opportunity for adequate correction while limiting the multiple risks of massive blood transfusions. The best example of the efficiency of this combination of efforts is the specific interest in spinal deformities in patients who are Jehovah’s Witness. Over the past 2 years, with the help of the bloodless program of Beth Israel Medical Center in New York, physicians were able to treat 22 patients with severe spinal deformities whose families could not accept any homogenous blood products. This series is currently under review but demonstrates that with a combination of efforts, blood transfusions could be minimized. Published studies demonstrate that aprotinin is a significant part of this endeavor.

Few studies have addressed the use of aprotinin in spine surgery. Reports reviewed in this article involve different methodologies and concern different types of patients. The message from these studies is that aprotinin reduces blood loss during spinal reconstructive surgery, but several questions remain. The dosage and the protocol of administration of the drug are highly variable and have to be codified. The risks of treatment have been clearly disclosed. However, as few adverse events have been reported to date, the populations studied are small and adverse events may be observed as the use of the drug becomes more widespread. The use of aprotinin should be reserved for patients with high risk of severe blood loss such as adult reconstructive multistage procedures, or children with nonidiopathic scoliosis. Such a limitation seems reasonable at this stage to minimize expenses and avoid unnecessary exposure to the drug that could jeopardize its use in the future (potential hypersensitivity). The efficiency of the drug should not minimize the importance of the other traditional techniques and precautions to prevent blood loss and limit transfusion in the perioperative period.

References

Lentschener C, Cottin P, Bouaziz H, et al. Reduction of blood loss and transfusion requirement by aprotinin in posterior lumbar spine fusion. Anesth Analg. 1999; 89:590-597.
Urban MK, Beckman J, Gordon M, et al. The efficacy of antifibrinolytics in the reduction of blood loss during complex adult reconstructive spine surgery. Spine. 2001; 26:1152-1156.
Karapurkar A, Kudalkar A, Naik L. Aprotinin to reduce perioperative blood loss in scoliosis surgery. Indian J Anaesth. 2002; 46:378-380.
Cole JW, Murray DJ, Snider RJ, et al. Aprotinin reduces blood loss during spinal surgery in children. Spine. 2003; 28:2482-2485.

Authors

From the Spine Institute, Beth Israel Medical Center, New York, NY.

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