Refractory Hypotension and Rapid Onset AKI: Deadly Complication After Doxorubicin and Mitomycin-C HIPEC Therapy

Introduction

Cytoreduction surgery with hyperthermic intraperitoneal chemotherapy (HIPEC) is now a standard procedure of choice for malignancy of female genital tract, colorectal carcinoma, appendicular neoplasms, and pseudomyxoma peritonei [1, 2]. The advantage of this combined procedure is removal of primary tumor followed by eradication of residual tumor cells by local effects of heated chemotherapeutic agents [3, 4].

We here present a case with severe hypotension and acute renal failure after mitomycin-C/doxorubicin combination during HIPEC procedure.

Case Report

A 71-year-old female patient without any comorbidity presented to the surgical emergency department with a chief complaint of diffuse abdominal pain. As per the computer tomography report, the patient had a peripherally enhancing lengthy appendix with a retrocecal position measuring 3.5 × 2.3 cm with a non-enhancing wall defect of 10 mm. The patient was diagnosed with a mucinous neoplasm of the appendix for that cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (HIPEC) [1] was planned. In pre-operative period, the patient was conscious oriented with stable vitals, and all system examination within normal limit except the pathology mentioned. The patient and family members were counselled about the nature of the surgery. She was also advised to improve her diet. She was prescribed incentive spirometry to avoid postoperative pulmonary complications such as atelectasis. During the preoperative period, the patient was adequately hydrated by administering intravenous fluid that was titrated to target urine output.

Her blood investigations (complete blood count, serum electrolytes) before surgery were within normal range with hemoglobin of 11.2 gm/dl. She had normal kidney function test (serum urea 10 mg/dl, s. creatinine 0.77 mg/dl). Her coagulation profile and liver function test were within normal limits with serum albumin of 3.97 gm/dl. Her chest X-ray, electrocardiogram, and echocardiogram did not show any abnormality. Pulmonary function test could not be done because of her poor cooperation. The procedure was performed under general anesthesia with a thoracic epidural in situ. The patient underwent omentectomy, splenectomy, total peritonectomy, and hysterectomy with bilateral salpingo-oophorectomy followed by HIPEC for 90 min with chemotherapeutic agent doxorubicin and mitomycin-C. Before and after the HIPEC procedure, the volume of fluid administration was titrated, targeting urine output as desired. Intraoperatively, a total of 10 L of crystalloid was administered with blood loss estimated at 200–300 ml and urine output of 1500 ml. Due to the unavailability of advanced monitoring like cardiac output monitor measuring stroke volume variation (SVV), central venous pressure (CVP) was used intraoperatively and maintained within the range of 8–12 cm H2O. The lactate in arterial blood gas was 3.66 mmol/L. The patient had intraoperative hypotension, for which she was started on noradrenaline infusion. The patient was shifted to ICU for further management without extubation. The patient was initially managed with fluid boluses and packed red blood cells. But the patient ultimately went into severe shock and anuria. The patient had conjunctival chemosis, and bed side ultrasonography showing multiple B line in lung USG and IVC was more than 2.5 cm and no variability with respiration. There was no postoperative surgical site bleeding as there was no frank blood through drain and not significant drop in hemoglobin level and hematocrit. Coagulation profile in the 1st post-operative period was within normal limit, though there was abdominal drain which is serous in nature as there was total peritoneal resection. The patient had losses from the abdominal drain which is serous in nature and replaced with adequate fluid resuscitation. Ultimately, second vasopressor, i.e., vasopressin, was started due to refractory hypotension. The patient was started on continuous renal replacement therapy for anuria due to dual vasopressor support. But the patient could not be revived after all resuscitative measures and expired.

Discussion

Weissberger, in the year 1955, was the first person to evolve the concept of intraperitoneal chemotherapy [2]. This complex procedure involves resection of the primary tumor with peritonectomy, omentectomy, and the installation of heated chemotherapeutic agents [3]. Local administration of heated chemotherapeutic agents has advantages like lesser systemic toxicities and heat on cellular function. The impact of hyperthermia on tumor cells comprises a change in the shape of the cell, decreased protein synthesis, protein denaturation, inhibit DNA and RNA synthesis, impaired cellular metabolism, altered gene expression, and signal transmission [4].

In addition to the long duration of the surgical procedure, there are many adverse effects. These are due to absorption of drugs, and solvent into the peritoneum leads to post-procedure nausea, vomiting, and a negative impact on wound healing and organ function and renal adverse effect with platinum-based chemotherapeutic agents [4]. Hyperthermia increases the body’s metabolic rate with increased oxygen consumption and production of carbon dioxide and ultimately leads to hyperlactemia [4, 5]. According to perioperative consensus guidelines for patients undergoing these surgeries, preoperative optimization with appropriate knowledge regarding the possible adverse effect of chemotherapeutic agents is essential for this complex procedure’s success [6].

As per one retrospective study conducted by taking data of 133 patients underwent cytoreductive surgery with HIPEC, 15.7 ml/kg/h is the fluid cutoff rate above which there is more risk of complications [7]. In our case, the total fluid administered during the 11-h procedure was 10 L due to the ongoing third space loss caused by the peritonectomy and to maintain urine output. Throughout the procedure, mean arterial pressure was maintained above 65 mm Hg with fluids and noradrenaline infusion, and urine output was maintained above 1 ml/kg/min. Due to total peritoneal resection, the patient had a loss of fluid from the peritoneum during the intraoperative and postoperative period. The patient had hypotension during the procedure, and the dose of noradrenaline gradually increased in the ICU, and vasopressin was started. But the patient had signs of fluid overload in the post-operative period, i.e., conjunctival chemosis along with multiple B lines in ultrasonography. Only test dose was given in the epidural, but there was no hypotension, tachycardia, and ST-T changes. Drug was not started through epidural in view of intraoperative hypotension. The patient’s renal function worsened in a shorter period after the HIPEC procedure, and continuous renal replacement therapy was initiated as the patient was hemodynamic unstable. The patient expired despite a maximum dose of vasopressor and fluid therapy. In this case, doxorubicin and mitomycin-C were used as chemotherapeutic agents during HIPEC. However, post-HIPEC acute renal failure is a known complication after cisplatin therapy, but acute renal failure after doxorubicin/mitomycin-C is not that common. The development of AKI in our case may be emphasized by the sequence of events and correction of all possible causes causing severe hypotension in this patient to provide a clue about this complication following doxorubicin and mitomycin-C combination in HIPEC technique.

Conclusion

Severe hypotension resistance to multiple vasopressor agents and acute renal failure could be complications after the doxorubicin-mitomycin-C combination HIPEC procedure. Anesthetists, surgeons, and the intensivist should be more vigilant for this rare complication and plan accordingly.

Declarations

Consent for Publication

Informed written consent has been obtained from patient for publication.

Conflict of Interest

The authors declare no competing interests.