TRAGIC EVENTS SURROUNDING CHRONIC HEMODIALYSIS PATIENTS IN CROATIA

Vladimir Gašparović1, Rajko Ostojić1

1 Department of Medicine Rebro, Zagreb University Hospital Centre, Zagreb, Croatia

key words: chronic hemodialysis, sudden deaths, perfluorocarbon

SUMMARY

Until recently mortality rates of chronic hemodialysis patients in Croatia was 10,26% and did not greatly differ from those in other countries. The tragic events that occurred in October 2001 resulted in 23 unexpected deaths of patients on chronic hemodialysis in a single week. Five patients died during hemodialysis and an additional 18 patients died within several hours after hemodialysis had been completed. The clinical presentation was characterized by dyspnea and hypotension, followed by cardiac arrest. Standard resuscitation measures were unsuccessful. These deaths pointed to an acute incident which had to be promptly identified in order to prevent further loss of life. To illustrate how dramatic these incidents were, let us just say that five patients died in a small regional center in a single day.

Once the initial epidemiologic data was obtained, simulation of hemodialysis on a model was performed. In all 23 patients who died during or shortly after hemodialysis P15 or P18 dialyzers were used. The mentioned dialyzers (P15 and P18) were manufactured by Baxter and distributed by Pliva. Effluent samples were gathered to be study by gas chromatography.

Dialysate, AV lines, water and staff were different and no correlation was found between these factors and the deaths. Fourteen patients underwent an autopsy. The autopsy findings consistant with end stage renal disease were found as were unusual foaming of blood and dilatation of heart chambers. According to the data provided by the manufacturer, perfluorocarbon which is used in the fiber stabilization process in the mentioned dialyzers may be responsible for the noted clinical picture since similar observations were made in an experimental model.

INTRODUCTION

The most commonly reported causes of in patients of chronic hemodialysis are cardiovascular incidents independent of extracorporeal circulation. Reactions to hemodialysis are most commonly allergic in origin, but according to available data they occur mainly at its beginning and do not result in a lethal outcome (1). Sudden death on hemodialysis is not frequent, and the literature reports mainly cardiovascular events as causes of death in chronic renal failure patients on hemodialysis (2,3). A number of reactions to hemodialysis have been noted, but as a rule without a lethal outcome. These are usually allergic reactions to a foreign substance (4,5). End-stage renal failure in Croatia is mainly managed with chronic intermittent dialysis in centers for dialysis, most often found in hospitals. Home hemodialysis is still underdeveloped (only six patients). According to the year 2000 annual report 2270 patients with chronic renal failure were dialyzed in Croatia. Of these, 143 were on peritoneal dialysis, and all others were on hemodialysis. The reported mortality rate was 10.26% (7). Mortality rates of patients on chronic hemodialysis in our country do not differ from those in the world. Information about four sudden deaths that occurred in one day, October 12, 2001, in the Center for Hemodialysis in the Požega General Hospital, pointed to the gravity and tragedy of events to follow. Once a connection with dialysis centers throughout Croatia was established, we were unfortunately faced with 24 fatal events, most of which were unexpected. Immediately upon arrival of the first epidemiological data we started to investigate the causes and found one common factor - dialyzer manufactured by Baxter/Pliva.

Patients and methods

A questionnaire made up of general and specific information was distributed among hemodialysis centers in which deaths had been reported. The clinical presentation, time at the which the incident was reported, previous medical history, type of hemodialysis equipment, types of membranes used, as well as solution types, specific AV lines and needles composed the data that was thoroughly analyzed. Autopsy findings were also recorded. One of the patients dialyzed on the hemofane membrane committed suicide and was therefore excluded from the investigated group.

The remaining 23 patients were dialyzed in six different centers throughout Croatia (Zagreb, Požega, Karlovac, Rijeka, Dubrovnik, Pula) on cellulose diacetate membrane P15 (15 patients) and P18 (eight patients). One patient in this group who died five hours after the beginning of dialysis had metastatic uterine cancer with ascites, but she was still in a satisfactory condition and ambulatory. Upon completion of dialysis the patient went home and died. Despite her malignant disease, her death was not immediately expected. The previous medical history of another patient was significant for an acute myocardial infarction eight days prior to death. Dialysis was performed with the P18dialyzer, and as in the former patient the death was unexpected. Death occurred 37 hours after the dialysis, and it is not certain that these two cases are associated with the dialyzer (Table 1). In all other patients on chronic hemodialysis, i.e. 21 patients, death was unexpected and was found to be associated with the dialyzer because all other materials were different (water, dialysis solutions, AV lines, needles, devices). All preserved incriminated dialyzers P15 had the same control number 2001 F 07 P (11 pieces), and dialyzers P18, on which the events occurred, probably the same control number 2001 B 17 R, manufactured by Baxter, distributed by Pliva.

Gas chromatography determined certain differences between the effluents taken from the incriminated dialyzers P15 and P18 when compared to the same type of dialyzers but with different control number.

The quality of water used for dialysis purposes was investigated by conductivity and the values ranged from 0 to 10.1 microsiemens.

Examination of the concentrate matched the declaration on the solution label. In patients who underwent an autopsy, in addition to findings commonly seen in chronic end-stage renal failure, foaming of blood in heart chambers and dilation of heart chambers was noted. At an autopsy in Požega, opening of the heart under water resulted in copious release of air bubbles from the heart.

Effluent samples from the incriminated dialyzers P15, control number 2001 F07 P, were marked by different findings of gas chromatography, i. e. the presence of a substance (peak) not found in the control cellulose diacetate dialyzers of the same manufacturer but of a different control number. Collected data on used devices, type of bicarbonate capsules, hemodialysis solutions, AV lines, needles and methods of device disinfection were different. According to the data provided by the manufacturer, the perflourocarbon solution used for fiber stabilization for the mentioned dialyzers is a volatile solution which under certain circumstances can assume a gaseous form.

The results are presented in table 1.

Discussion

Mortality of patients on hemodialysis in the world is 9-10%, and in Croatia it does not substantially differ from this number According to the national annual report the mortality rate in chronic hemodialysis patients in Croatia is 10.26% (6).

The unexpected deaths among hemodialysis patients in Croatia that occurred within a week led to a medical crisis. These events alarmed all hemodialysis patients, their families as well as the medical personnel and the media throughout Croatia. They led to the resignation of the Croatian Minister of Health and will certainly have legal consequences. Once the problem was identified appropriate measures were undertaken, yet the death toll of these tragic events remains a horrific reminder(7,8).

Problems with cellulose acetate membrane were consequent to long storage of a dialyzer, and were characterized by eye redness and tearing, loss of hearing, tinnitus and pain in the bones (1-5).

On the day of the first noted death the hemodialysis procedure started in the usual fashion. The events that followed occurred rapidly. Patients complained of chest pain and dyspnea. Five deaths occurred during hemodialysis. An additional 16 patients died within 10 hours of hemodialysis completion. Only two patients died more than 10 hours after hemodialysis.

The clinical picture was dominated by suffocation, chest pain, sweating, and in 2 cases with generalized convulsions. Clinical manifestations of dyspnea and restlessness lasted briefly from the beginning of the event to cardiac arrest, most often less than 30 minutes. All incidents resulted in a lethal outcome despite resuscitation attempts in hospital settings. Some patients went home without complaints, and according to the information provided by family members the presentation corresponded to in-hospital deaths. Similar incidents happened in two Spanish towns, Madrid and Valencia, but data concerning these incidents is not quite clear (9). According to an oral communication by the representative of the Food and Drugs Administration (FDA), there were two deaths during hemodialysis in the U.S.A., and two patients were hospitalized with severe respiratory problems, so that in at least one case artificial ventilation was needed. No satisfactory explanations of these events were offered (10). The patients in Croatia were dialyzed on monitors from different companies with different solutions produced by different manufacturers. Different AV lines, needles, as well as vascular accesses, were used. Information concerning incidents related to certain Baxter and Althin monitors secondary to blood acidification was not applicable to the Croatian setting because we use a bicarbonate powder for alkalinization.

Collection of epidemiological data was impeded by the brevity of time in which the events happened, as well as by insufficient communication between centers for dialysis. All elements including the sudden occurrence of the incident, very similar clinical manifestations, unsuccessful resuscitations, autopsy findings, different consumables in the dialysis procedure pointed to the only common factor in these tragic events: cellulose diacetate membrane manufactured by Baxter. There have been no reports in the literature in which the mechanism of such events was disclosed. This includes the reports from Spain.

Sudden deaths on hemodialysis or in the first hours after dialysis are related with cellulose diacetate dialyzers manufactured by Baxter, distributed by Pliva, named P15 and P18.

The clinical presentation pointed to a possible gas embolization of both the arterial and the venous circulation. The macroscopic autopsy findings from Pula and Požega Centers pointed to gas embolization of the great arteries and foaming of blood within both the arterial and venous pools. These reports were crucial for our investigation to focus on possible causes of gas embolism. According to the most recent communication by the manufacturer, it is possible that the liquid for preparation and stabilization of fibers, perfluorocarbon PF 5070, is responsible for these events. This liquid is used in Sweden for stabilization of fibers for dialyzers Althin, which Baxter has in the meantime taken over (11). The offered information pointed that a 1 μl of perflourocarbon may produce up to 1 ml of gas, which is a 1000 fold volume enlargement. It would seem that flushing the filter with a 1000 ml of normal saline enabled small quantities of perflourocarbon to remain within the filter. These would turn to their gaseous form once they entered the blood stream and produce gas embolisms. These results suggest that a serious manufacturing error has been made and that the manufacturing process need to be radically altered.

After the withdrawal of P15 and P18 dialyzers no new dialysis deaths have been recorded in our country. We believe that the identification of the incriminated substance is of paramount importance for the prevention of such future tragedies.

LITERATURE:

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2.  Takeda K, Harada A, Okuda S, Fujimi S, Oh Y, Hattori F, Motomura K, Hirakata H, Fujishima M. Sudden death in chronic dialysis patients. Nephrol Dial Transplant 1997; 12(5):952-5.

3.  Cohle SD, Graham MA. Sudden death in hemodialysis patients. J Forensic Sci 1985; 30(1):158-66.

4.  Noh H, Lee YK, Kan SW, Choi KH, Ha DS, Lee HY. Acute eosinophilic pneumonia associated with amitriptyline in a hemodialysis patient. Yonsei Med J 2001; 42:357-9.

5.  Moore MA, Kaplan DS, Picciolo GL, Wallis RR, Kowolik MJ. Effect of cellulose acetate materials on the oxidative burst of human neutrophilis. J Biomed Mater Res 2001; 55:257-65.

6.  Kaštelan A. Annual report of Croatian center for dialysis and tissue transplantation in Croatia in 2000, Zagreb, Urology Clinic, 2001.

7.  Marušić Ana, Croatian Health Minister resignts after dialysis deaths. Lancet 2001;338:1431,

8.  V. Gašparović, R. Ostojić, Ira Gjenero-Margan, P. Kes. Sudden deaths in chronic renal failure patients on haemodialysis in Croatia. Cro Med J, 2001; 42:606-610

9.  Bosch X: Baxter withdraws dialyser after 12 patients die; Fatal incidents on hemodialysis in Spain, BMJ. 2001; 323:529-529a.

10. CDC Conference Bridge Confirmation, FDA, Conference call. Oct 17, 2001.

11. Baxter; Corporate news: Following extensive investigation, Baxter identifies probable cause of recent hemodialysis patient deaths, November 5, 2001