Survival of patients with acute renal failure requiring dialysis after open heart surgery: Early prognostic indicators

nts with acute renal failure ysis aafter open heart surgery: Early indk&brs

Survivd requiring prognostic

We analyzed pre- and postoperative data from 36 consecutive patients, who developed acute renal failure requiring hemodialysls after open heart surgery, to determine which factors predicted survival. Seventeen patients (47%) survived. Age, 88x, preoperative renal dysfunction, severity of underlying heart disease, pertoperative myocardial inftarction, cardiopuimonary bypass time, and olguria did not influence outcome (by univeriate anakyeia). However, the number 8nd type of postoperative complications, before the first hemodialysis and 48 hours thereafter, were found to be significant predictors of outcome. Univariste 88 well as multivariste analysis showed that the highest mortality rate was asoociated with the presence of respiratory failure, central nervous system dysfunction, hypotenston, and infection (48 hours after fir8t hemodiarysis). Thirty-three (92%) of the 36 patients were correctly classified as survivors or nonsurvivors based on the presence or ebrence of any one of three progno8tic indicator8 (three or more complications before the first hemodialysis and PerSiSUng 48 hours leter; hypotension before the first dfalysis and perristing 48 hours later; or central nervous system dysfunction 48 hour8 after hemodialysis was initiated). We conclude that an asses8ment of prognosis can be made tn such patients as early 88 48 hour8 after the first hemodi8ly8~a bssed on the number and type of complications. (AM HEART J 1987;113: 1138.)

Helmut W. Lange, M.D., Dorothee Minneapolis, Minn.

M. Aeppli,

Ph.D., and David C. Brown, M.D.

Severe acute renal failure requiring hemodialysis develops in about 2 % of patients undergoing cardiac surgery.” 2,4*6-10Whereas earlier series have indicated a mortality rate of 70% to 100% in these patients,‘+ a few recent reports have suggested an improved prognosis?-lo In view of the physical, psychological, and financial impact of this complication, prognostic indicators which could aid in treatment planning and decision making in these critically ill patients are highly desirable. Although previous data have shown that certain variables (age, oliguria, clinical complications) are associated with a higher mortality ra@v3’9,11~12 no clinical study has yet identified prognostic indicators early in the course of acute renal failure which could predict outcome with reasonable certainty. Therefore, we reviewed the records of 36 consecutive patients who had undergone cardiac surgery and developed acute renal failure requiring hemodialysis postoperatively, in search of predictors of outcome.

From the Department versity of Minnesota. Received

for publication

of Medicine, March

Abbott 17, 1986;

Northwestern accepted

Sept.

Hospital, 24, 1988.

Reprint requests: David C. Brown, M.D., Abbott Northwestern 800 E. 28th St. at Chicago Ave., Minneapolis, MN 55407

1138

Uni-

Hospital,

METHODS

Between July, 1980, and October, 1983,a total of 2959 patients underwent cardiac surgery at our institution. Thirty-six patients (1.2% ),22 men and 14women (ages21 to 84 years, mean69 years), met our criteria for inclusion in this study. Thesecriteria were: (1) age 18years or older, (2) absenceof chronic renal failure treated with hemodialysis prior to surgery, (3) postoperative survival for more than 48 hours, and (4) severeacute renal failure requiring hemodialysis. Types of surgery preceding the development of acute renal failure were: coronary artery bypass graft surgery (12 patients), valve replacement (10 patients) or both (12 patients), composite graft replacement of ascendingaorta (one patient), and repair of the thoracic aorta (one patient). Indications for hemodialysis were fluid overload, hyperkalemia (unresponsive to administration of exchangeresins),or blood urea nitrogen exceeding 80 mg/dl in the absenceof pre- or postrenal failure. All patients were treated by the samenephrology team in the surgical cardiovascular intensive care unit. Principles of treatment included early and frequent dialysis, administration of H, blockers, and early use of intravenous hyperalimentation. Dialysis was performed with a single-patient, singlepassdelivery system. Bicarbonate was used as the base. Potassiumconcentration in the dialysate varied with the predialysis serumpotassiumconcentration. Various capillary dia.lyzerswere used depending on the stability of the patient and the need for diffusion and ultrafiltration.

Volume Number

113 5

Blood flows of 175 ml/min were usedfor the first dialysis, and subsequent flows to 250 ml/min were used if the patient was stable enough. Length and frequency of dialysis were tailored to clinical need, but ordinarily dialysis lasted 4 hours and was performed daily initially and then every other day as the patient became more stable. Two of the 36 patients, in whom dialysis was necessary before anticoagulation was possible, were treated with peritoneal dialysis and then switched to hemodialysis. Preoperative variables. These were age,sex, history of hypertension or diabetes mellitus, serum creatinine, ejection fraction, pulmonary wedge pressure, and presence and severity of coronary artery disease(number of coronary arteries with greater than 60% luminal narrowing as assessed by preoperative cardiac catheterization). Perioperative variables. These were cardiopulmonary bypasstime, aortic cross-clamptime, postoperative hypotension (use of intravenous inotropic drugs for a systolic arterial blood pressurelessthan 90 mm Hg in the recovery room), postoperative pulmonary wedge pressure (in the recovery room), and perioperative myocardial infarction (development of new Q waves or greater than 1 mm descendingST segmentdepressionpersisting more than 48 hours postoperatively, or a postoperative peak myocardial specific creatinine kinase level of more than two standard deviations above control levels in the absenceof valvular surgery). Prehemodialysis variables. These were the postoperative day of the first hemodialysis, serum creatinine and blood urea nitrogen prior to hemodialysis, and urine output during the 24 hours preceding the first hemodialysis. Postoperative complications. These were analyzed immediately prior to the first hemodialysis,48 hours later, and at 4 and 6 days after the first hemodialysis. The six complications analyzed are defined as follows: (1) respiratory failure = use of mechanical ventilatory support; (2) infection = administration of intravenous antibiotics for a body temperature exceeding38.5”C associatedwith bacteriologic or radiologic evidence of infection; (3) central nervous system dysfunction = inability of the patient to respond appropriately to verbal commands (stupor); (4) hypotension = use of intravenous inotropic drugs for a systolic arterial blood pressure lessthan 90 mm Hg; (5) bleeding = clinically detectable hemorrhage during the preceding 24 hours necessitating the administration of erythrocyte transfusions; (6) jaundice = total serum bilirubin exceeding 5 mg/dl. Follow-up information was obtained by telephone from the physician who continued the care after discharge. No patient was lost to followup* Statistical analysis. Continuous variables are summarized by meansand standard deviations and comparisons evaluated by Student’s t test. Discrete variables are described by relative frequencies and relative risks and compared by means of chi-square tests with continuity correction. Relative risks (rate of death in the presenceof a particular risk factor divided by the rate of death in its absence)are reported only for comparisonswhich yielded

Acute

renal failure

after open-heart

surgery

1139

I. Preoperative variables

Table

Variables

n

Survivors

Nonsurvivors

p Value

36 19

68 + 14 10 (53)

69 k 9 9 (47)

NS NS

1215

1019

10 (48)

11 (52)

NS NS NS

Age W

Mean >70

Sex (M/F ratio) 36 Hypertension 21 Diabetes mellitus 5 Serum creatinine (mg/dl)

Mean

2 (40)

3 (60)

NS

36 19

2.0 k 1.5 9 (47)

1.4 + 0.4 10 (53)

NS

Ejection fraction (%) Mean 33

55 + 14

55 ir 16 7 (54)

NS NS

5 (42)

18 f 9 7 (58)

NS NS

2.1 + 1.2 13 (52) 9 (53)

1.7 + 1.4 12 (48) 8 (47)

NS NS NS

>1.3

<50

13

6 (46)

Pulmonary wedge pressure (mm Hg) Mean 34 17 k 7 >18

12

CAD (vessel/patient)* Mean 34 11 25 3

17

Values are means + 1 standard deviation. Numbers in parentheses are percentages with respect to “n” (n = number of patients in whom a particular variable was analyzed); NS = not significant. *Coronary artery disease; ~1 = at least one significant stenosis; 3 = threevessel disease.

significant (p < 0.05) differences. Stepwise logistic regression (BMDP routine, Biomedical Computer Programs, University of California Press, 1983, Berkley, CA) was usedto examine multiple complications. The 0.05 level of probability was usedas the criterion of significance. RESULTS

In the total study group, 17 patients (47%) survived and 19 (53%) died. Preoperative variables. The mean age of survivors was not different from that of nonsurvivors (68 + 14 years vs 69 -t 9 years). Age greater than 70 years did not carry a significant mortality risk (by univariate analysis). Sex, hypertension, and diabetes mellitus had no significant impact on survival, neither did preoperative renal dysfunction (serum creatinine exceeding 1.3 mg/dl). Preoperative parameters of ventricular function (ejection fraction, pulmonary wedge pressure) were similar among survivors and nonsurvivors, and abnormal ventricular function preoperatively (ejection fraction less than 50 % , pulmonary wedge pressure greater than 18 mm Hg) was not associated with a higher mortality risk. Coronary artery disease was present in 25 of 34 patients who had preoperative coronary angiograms; neither the presence nor the severity of coronary artery disease adversely affected chances of survival (Table I). Perioperative variables. The mean cardiopulmonary bypass time and aortic cross-clamp time were

May1987 1140

Table

Lange, Aeppli, and Brown

American

Journal

II. Perioperative variables Variables

Cardiopulmonary bypass time (min) Mean >120 Aortic cross-clamp time (min) Mean >60 Postoperative hypotension Postoperative pulmonary wedge pressure Mean >18 Perioperative myocardial infarction

n

Survivors

35

142 ir 56 9 (50)

132 + 58

67 f 26

67 +- 31

10 (50)

10 (50) 12 (60)

18

35 20 20 (mm Hg) 32 13 10

Values are means ? 1 standard deviation. Numbers in parentheses are percentages with respect to “n” (n = number

Table

Heart

Ill. Prehemodialysisvariables

Variables

n

Survivors

Nonsurvivors

Postoperative day of first hemodialysis 6~2 7k5 Mean 36 >6 12 5 (42) 7 (58) Serum creatinine (mg/dl) Mean 36 6.5 + 2.4 5.2 z!z 1.8 >6 15 9 (60) 6 (40) Blood urea nitrogen (mg/dl) Mean 36 77 + 19 87 k 43 >80 15 10 (67) 5 (33) 24-hour urine (ml) Mean 36 895 k 599 888 + 630 <400 9 4 (44) 5 (56)

p Value NS NS NS NS NS NS

NS NS

Values are means k 1 standard deviation. Numbers in parentheses are percentages with respect to “II” (n = number of patients in whom a particular variable was analyzed); NS = not significant.

similar for survivors and nonsurvivors. Neither a bypass time exceeding 2 hours nor an aortic crossclamp time exceeding 1 hour was associated with significant relative risk. In the immediate postoperative period, hypotension was present in 20 patients and the pulmonary wedge pressure was elevated (above 18 mm Hg) in 13 patients; neither of these was found to have an adverse effect on survival. Seven of 10 patients with perioperative myocardial infarction died, but the associated relative risk did not reach statistical significance (Table II). Prehemodiatysis variables. Hemodialysis was started at a similar postoperative day in survivors and nonsurvivors (6 & 2 vs 7 + 5 days). Initiation of hemodialysis after the sixth postoperative day did not influence outcome. The degree of axotemia prior to hemodialysis did not result in survival differences. Oliguric acute renal failure (24-hour urine volume less than 400 ml) was present in nine

Nonsurvivors

NS NS

9 (50)

8 (40) 16 k 6 5 (38) 3 (30)

of patients

p Value

NS NS NS NS NS NS

17 Ik 7

8 (62) 7 (70)

in whom a particular

variable

was analyzed);

NS = not significant

patients (25%)) and was not associated with significant differences in outcome (Table III). Postoperative complications. The number and type of postoperative complications, which were present before the first hemodialysis as well as 48 hours later, were found to be associated with significant differences in survival rates (Table IV). Before the first hemodialysis, 12 (33%) of all patients were free of any of the six complications under study. The relative risk was significantly lower, that is, chance of survival was better, for patients free of complications compared to those who had a least one complication (relative risk 0.2, p < 0.01). With an increasing number of complications survival rates decreased. Forty-eight hours after the first hemodialysis, the number of patients without complications increased only in the group of survivors (from 10 to 13), whereas it remained the same among nonsurvivors (two patients). Univariate analysis of the influence of each complication showed that before the first hemodialysis, respiratory failure (p < 0.01) and infection (p < 0.05) could serve as significant predictors of nonsurvival. Forty-eight hours after the first hemodialysis, the predictive power of respiratory failure was increased, and central nervous system dysfunction and hypotension emerged as two additional complications with significant risk, because in the survivor group respiratory failure resolved in two patients, central nervous system dysfunction improved in one patient, and hypotension resolved in two patients, whereas in the nonsurvivor group, the number of patients with respiratory failure remained the same, four more patients developed central nervous system dysfunction, and in only one patient was hypotension resolved. At 4 and 6 days after initiation of hemodialysis, the risk carried by

Volume Number

113 5

Acute renal failure after open-heart

Table IV. Outcome in 36 patients with acute renal failure postoperative complications (before the first hemodialysis

after open heart surgery related and 48 hours later)

Before first hemodialysis

to number

surgery

1141

and type of

48 hours later

n

Survivors

Nonsurvivors

Relative risk

p Value

n

Survivors

Nonsurvivors

Relative risk

p Value

All patients No. of complications 0

36

1’7 (47)

19 (53)

*

-

36

17 (47)

19 (53)

*

-

12

10 (83)

13 11

‘346)

2 (17) 7(54) lO(91)

0.2 * 2.5


15 10 11

13(87) 4(40) O(O)

2W

l-2 r3 Type

6(60) ll(100)

0.2 * 3.1


18 14 7

4(28) WW

14(78) ll(70) 6(86)

2.8 2.2 *


NS

16 14 10

O(O)

14(88) ll(79) lO(100)

3.5 2.2 2.9


10

xw W2) 1(20)

8(80)

*

7(88) 4(80)

* *

NS NS NS

7 3 6

O(O) O(O) 107)

7wO) 3(100) 5(83)

2.4 * *

<0.02 NS NS

of complication Respiratory failure Infection Central nervous system dysfunction Hypotension Bleeding Jaundice

Numbers *Relative

8 5

l(9)

104)

in parentheses are percentages with respect to “n” (n = number of patients risk for the intermediate category was not computed; it could be interpreted

each complication did not change significantly, except for infection which posed an increased risk on day 6 (relative risk 4.8, p < 0.01). The results of univariate analysis of postoperative complications were confirmed by multivariate analysis (multiple stepwise regression), which showed that 48 hours after the first hemodialysis, respiratory failure, central nervous system dysfunction, hypotension, and infection were the most important determinants of survival (approximate F values 21.5,17.8,9.4, and 6.9, respectively), whereas bleeding and jaundice did not contribute significantly to the outcome (approximate F values 3.0 and 2.8, respectively, p not significant). A combination of three prognostic indicators, based on the number and type of postoperative complications before and 48 hours after hemodialysis, correctly classified 33 of the 36 patients into survivor and nonsurvivor categories. These prognostic indicators were: (1) a persisting high number of complications (three or more complications before the first hemodialysis and persisting 48 hours later); (2) hypotension (before the first hemodialysis and persisting 48 hours later); (3) central nervous system dysfunction (48 hours after hemodialysis was initiated). In the presence of any one of these prognostic indicators all patients had a fatal outcome (positive predictive value 100%). In contrast, 17 of 20 patients in whom none of these indicators were present survived (negative predictive value 85%). Sensitivity and specificity of this predictive model were 84 % and 100%) respectively (predictive accuracy 92%) p < 0.0001).

2W) WU

in whom a particular variable was analyze,& NS = not significant. because there was more than one group for comparison.

Clinical course. In 16 (94%) of 17 survivors, renal function recovered .to a degree where hemodialysis could be discontinued. The 16 survivors who recovered adequate renal function were treated with hemodialysis over a period of 21 + 19 days (range 1 to 85 days) with an average number of 12 f 11 treatments/patient (range 1 to 54). Six (38% ) of these patients recovered from acute renal failure after a period of more than 3 weeks following the first hemodialysis. Nonsurvivors were treated over a period of 24 f 28 days (range 3 to 95 days with an average number of 15 -t 16 treatments/patient (range 1 to 55). Eleven (58 % ) of the 19 nonsurvivors died within 3 weeks after surgery, whereas death occurred between 3 weeks and 3 months in the remaining eight patients. Only two nonsurvivors recovered adequate renal function prior to death (12 and 28 days after hemodialysis was started). Follow-up. Three of the 17 hospital survivors died during an average follow-up period of 14 months (range of follow-up 3 to 30 months). AII three deaths occurred within the first year after discharge. The l-year survival rate was 8 of 11 (73%). DISCUSSION

This study differs in two ways from previous investigations concerning the prognosis of patients with acute renal failure after cardiac surgery. First, since the number of patients under study is larger than in previous series’-lo and the survival rate is approximately 50%) we were able to perform a meaningful statistical analysis of prognostic factors.

1142

Lange,

Aeppli,

and Brown

Second, although previous studies have already attributed a lethal outcome of patients with acute renal failure to the presence of complications.3p 8,g,11,l2 earlier investigators have reported the total incidence of complications during the entire clinical course. In contrast, we analyzed the prevalence of complications at defined points in time early in the clinical course as well as changes after initiation of hemodialysis. This approach seems to better reflect the situation which the clinician faces, and it takes into account the important prognostic information which may become evident during the patient’s course of treatment with hemodialysis. The overall survival rate of 47 % in our patients is in agreement with recent reports indicating a slightly improved prognosis for these patients?.lo This improved outcome is especially noticeable in view of the fact that the average age of our patients (69 years) is higher than that in previous series, reflecting the trend not to limit the indication for major cardiac surgery to patients less than 70 years of age. Furthermore, the high average age of our patients may have contributed to the result that age did not predict chances of survival, which contrasts with earlier reports8sg* l1 The relatively low incidence of oliguric acute renal failure in our patients (25% ) could have affected the overall outcome favorably, since it has been shown to be associated with a lower survival rates~g~12,l3 than nonoliguric renal failure. However, our data do not support this observation, since the survival rate of our oliguric patients was similar to that of our patients with nonoliguric acute renal failure. It appears unlikely that the relatively low mortality rate in our study was the result of an earlier start of treatment,14 since the values for serum creatinine and blood urea nitrogen before initiation of hemodialysis were similar to those in an earlier report.” Furthermore, the degree of azotemia at the start of hemodialysis did not appear to influence chances of survival. The duration of cardiopulmonary bypass and aortic cross clamping has been shown to correlate with the incidence of postoperative renal dysfunction as well as acute renal failure.2349 6 The average duration of cardiopulmonary bypass and aortic cross-clamping in our study is similar to that of patients studied by Abel et al4 However, these parameters do not seem to influence the prognosis, once acute renal failure has occurred. Our results indicate that neither pre- nor perioperative variables nor variables of renal function prior to the first hemodialysis have a significant impact upon survival and, consequently, these cannot serve as prognostic indicators. However, out-

American

May 1997 Heart Journal

come can be predicted even before the first hemodialysis on the basis of the number and type of complications present at that time. In the absence of any complications more than 80% of patients survived, while the presence of three or more complications was associated with a 90% mortality rate. Patients with respiratory failure or infection before initiation of hemodialysis carried a mortality risk approximately twice that of patients without these complications (relative risk 2.8 and 2.2, respectively). Complications which developed or persisted despite treatment with hemodialysis carried an even higher mortality risk. We feel that hemodialysis played a role in the correction of some complications. It is conceivable that complications responding to hemodialysis were caused by uremia or fluid overload, whereas etiologic factors not amenable to hemodialysis were responsible for fatal complications. This observation is in agreement with the results of a survey of 499 patients studied by Balslov and Jorgensen,15 who found that uremic central nervous system dysfunction usually responded within 48 hours to initiation of hemodialysis. The relative risk associated with the postoperative complications under study did not change significantly later than 48 hours after the first hemodialysis, with the exception of infection, which, became a more significant predictor at 6 days. Therefore, it appears reasonable to choose 48 hours after the first hemodialysis as the best time for an assessment of prognosis. At this point in the clinical course, univariate as well as multivariate analysis revealed that survival was largely determined by respiratory failure, central nervous system dysfunction, hypotension, and infection (in decreasing order of predictive power). Although neither bleeding nor jaundice as a significant risk factor, the number of patients with these complications was small. Based on the combined analysis of both the number and the type of complications before and 48 hours after the first hemodialysis, a predictive model was designed which allowed a correct classification of 33 patients into survivor and nonsurvivor groups (predictive accuracy 92 % ). In the presence of either three or more complications or hypotension (before and after hemodialysis) or central nervous system dysfunction (after hemodialysis) the mortality rate was lOO%, whereas in the absence of these predictors 85% of patients survived. We emphasize that we do not recommend the use of this predictive model to support the decision to withdraw hemodialysis therapy of critically ill patients who, based on these prognostic indicators, appear to have a hopeless prognosis. Judicious use of the increasingly

Volume

113

Number

5

limited financial resources for critically ill patients have been advocated, especially in view of their guarded long-term prognosis.16 However, we believe that, because of the complexity of the disease process in acute renal failure as well as the lack of prospective validation of our retrospectively designed analysis, prognostic information of suf& cient reliability is not yet available which could potentially justify withdrawal of therapy. Furthermore, our data indicate that the long-term prognosis of patients surviving acute renal failure after cardiac surgery appears to be better than that reported for patients with other critical illnesses.16 In our study, the l-year survival rate in patients leaving the hospital was 73 % . Nevertheless, prognostic information both for the physician as well as for the patient and relatives early in the clinical course is an essential part of the decision-making process in the care of critically ill patients.17 We have demonstrated that valuable prognostic information in patients with acute renal failure following cardiac surgery can be obtained from an analysis of complications as early as 48 hours after initiation of hemodialysis therapy.

Acute

5. 6. 7. 8. 9.

10. 11.

12. 13. 14.

REFERENCES

1. Doberneck RC, Reiser MP, Lillehei CW. Acute renal failure after open heart surgery utilizing extracorporeal circulation and total body profusion. Analysis of 1000 patients. J Thorac Cardiovasc Surg 1962;43:441. 2. Yeboah ED, Petrie A, Pead JL. Acute renal failure and open heart surgery. Br Med J 1972;1:415. 3. Casali R, Simmons RL, Najarian JS, von Haritizsch B, Buselmeier TJ, Kjellstrand CM. Acute renal insufficiency complicating major cardiovascular surgery. Ann Surg 1974;181:370. 4. Abel RM, Buckley MJ, Austen WG, Barnett GO, Beck CH,

15. 16. 17.

renal failure

after open-heart

surgery

1143

Fischer JE. Etiology, incidence, and prognosis of renal failure following cardiac operations. J Thorac Cardiovasc Surg 1976;71:323. Krian A. Incidence, prevention and treatment of acute renal failure following cardiopulmonary bypass. Int Anesthesiol Clin 1976;14:87. Bhat JG, Gluck M, Lowenstein J, Baldwin DS. Renal failure after open heart surgery. Ann Intern Med 1976;&1:677. Hilberman M. Mvers BD. Carrie BJ. Derbv G. Jamison RL. Stinson EB. Acute renal failure following cardiac surgery. J Thorac Cardiovasc Surg 1979;77:880. McLeish KR, Luft FC, Kleit SA. Factors affecting prognosis in acute renal failure following cardiac operations. Surg Gynecol Obstet 1977;145:28. McMurray SD, Luft FC, Maxwell DR, Hamburger RJ, Futty D, Szwed JJ, Lavelle KJ, Kleit SA. Prevailing patterns and predictor variables in patients with acute tubular necrosis. Arch Intern Med 1978;138:950. Gailiunas P, Chawla R, Lazarus JM, Cohn L, Sanders J, Merrill JP. Acute renal failure following cardiac operations. J Thorac Cardiovasc Surg 1980;79:241. Kennedy AC, Burton JA, Luke RG, Briggs JD, Lindsay RM, Allison MEM, Edward N, Dargie HJ. Factors affecting the prognosis in acute renal failure. A survey of 251 cases. Q J Med 1973;42:73. Baek S, Makabsli GG, Shoemaker WC. Clinical determinants of survival from postoperative renal failure. Surg Gynecol Obstet 1975;140:685. Anderson RJ, Linas SL, Berns AS, Henrich WL, Miller TR, Gabow PA, Schrier RW. Nonoliguric acute renal failure. N Engl J Med 1977;296:1134. Kleinknecht D, Jungers P, Chanard J, Barbanel C, Ganeval D. Uremic and nonuremic complications in acute renal failure: evaluations early and frequent dialysis on prognosis. Kidney Int 1972;1:190. Balslov JT, Jorgensen HE. A survey of 499 patients with acute anuric renal insufficiency. Causes, treatment, complications and mortality. Am J Med 1963;34:753. Cullen DJ, Ferrara LC, Briggs BA, Walker PF, Gilbert J. Survival, hospitalization charges and follow-up results in critically ill patients. N Engl J Med 1976;294:982. Wanzer SH. Adelstein SJ. Cranford RE. Federman DD. Hook ED, Moe&l CG, Safer PI Stone A, Taussig HB, vanEys J. The physician’s responsibility toward hopelessly ill patients. N Engl J Med 1984;310:955.