Risk factors for cardiovascular death within 30 days after anaesthesia and urgent or emergency surgery: a nested case-control study

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1 British Journal of Anaesthesia 82 (5): (1999) Risk factors for cardiovascular death within 30 days after anaesthesia and urgent or emergency surgery: a nested case-control study S. J. Howell 1, J. W. Sear 1 *, Y. M. Sear 1, D. Yeates 2, M. Goldacre 2 and P. Foex 1 1 Nuffield Department of Anaesthetics, John Radcliffe Hospital, Headington, Oxford OX3 9DU, UK. 2 Unit of Health Care Epidemiology, University of Oxford, Oxford, UK *Corresponding author The Oxford Record Linkage Study (an epidemiological database) was used to identify patients who died from a cardiovascular cause within 30 days of emergency or urgent surgery under general anaesthesia. Each case was paired with a control patient (matched for age within 10 yr of the patient, operation and consultant). Additional clinical information was sought from the patient s case notes. Cases and controls were compared for cardiovascular risk factors using conditional logistic regression analysis and a prognostic model was generated. Only one significant risk factor was identified in the final model: a history of cardiac failure (odds ratio 14.84; 95% confidence intervals ; P 0.003). Associations between a history of cerebrovascular accident or renal impairment and cardiovascular mortality were seen using univariate analysis but not after adjustment for confounding factors. Br J Anaesth 1999; 82: Keywords: anaesthesia, general; complications, mortality; complications, cardiovascular disease; anaesthesia, audit; records, anaesthesia Accepted for publication: December 7, 1998 We have reported previously on the use of the Oxford Record Linkage Study and review of clinical case notes to define some of the risk factors associated with cardiovascular death after elective non-cardiac surgery under general anaesthesia. 12 However, it is well established that the risk of mortality associated with urgent and emergency surgery is considerably greater than that after elective procedures. 3 5 Much of this increased risk may be because patients are seriously ill with the conditions for which the emergency procedure is indicated. Furthermore, co-morbidity may also play a significant part in postoperative outcome. In this study, we have examined those factors associated with perioperative cardiovascular mortality after urgent or emergency surgery using a case-control study design similar to that described in our previous article of risk factors for cardiovascular death after elective surgery. 2 Methods The Oxford Record Linkage Study (ORLS) covers approximately 1.9 million people within the former Oxford Regional Health Authority area. Further information on the ORLS has been described by Howell and colleagues. 2 In brief, it includes data on all hospital admissions and deaths in the area, linked for individuals, and can be used to analyse records of people who have both undergone operations and died. The population chosen for this study comprised patients who underwent urgent and emergency surgery under general anaesthesia in one of the three hospitals in Central Oxford or Banbury between 1987 and All patients were aged more than 18 yr and underwent non-cardiac and nonneurological operations. For the area covered by the ORLS (relative to England as a whole), the standardized mortality ratios (SMR) for diseases of the circulatory system were 85 for men and 89 for women in 1990; the corresponding SMR values for ischaemic heart disease were 83 and 81, respectively. We used the ORLS to identify patients who died within 30 days of anaesthesia and surgery after emergency admission to hospital. Patients whose death certificate included ICD9 codes (9th International Classification of Diseases) in the range inclusive, at any position on the death certificate were included. The diseases covered by these codes are: hypertensive heart disease ( ); ischaemic heart disease ( ); diseases of the pulmonary circulation ( ); other forms of heart disease ( ); and cerebrovascular disease ( ). We excluded patients dying from pulmonary embolism (415.1). There are also specific codes within the ICD9 relating to British Journal of Anaesthesia

2 Howell et al. complications associated with anaesthesia (e.g for shock as a result of anaesthesia, and cardiac arrest or insufficiency resulting from an operative procedure). As in our previous study examining mortality associated with elective anaesthesia and surgery, 2 these codes were not used as a certified cause of death in any patient. Controls For each patient at least one control was identified. Where possible, two or more controls were sought to allow for the possible non-availability of the medical case records. Controls were matched according to the following criteria: underwent the same operation as the patient; was under the care of the same consultant as the patient; and age within 10 yr of the patient. Where two control patients were identified, one was chosen at random and the notes obtained. If these were not available, or if this control was excluded for other reasons, the notes of the second control patient were then examined. Examination of medical records Before the study, we obtained consent from the consultant surgeon caring for the patient during admission for surgery to examine the records of the case and control patients. Where the consultant had died or retired, the consent of the successor was sought. The notes were examined in detail by a research nurse (Y. M. S.). Whenever possible, the cause of death was confirmed from the notes to ascertain that the cause on the death certificate was supported by the medical records. If the patient had not died from a cardiovascular cause, they were excluded from the study. Patient data and information on cardiovascular risk factors were also collected. Patient records were examined for the following risk factors. (i) Arterial hypertension and heart failure. A patient was defined as having one or both of these intercurrent conditions if they were receiving medication. Patients receiving diuretics, β-adrenoceptor blocking drugs, calcium channel antagonists or ACE inhibitors and whose notes suggested a history of arterial hypertension were classified as having hypertensive disease; those receiving loop diuretics and/or ACE inhibitors and whose notes suggested a history of heart failure were classified as such. If it was not clear if drugs had been prescribed for heart failure or hypertension, the issue was resolved by referring to other available data (such as other medications (e.g. β-adrenoceptor blocking drugs), the ECG and chest x-ray reports). Where the term hypertension is used in this article, it refers to treated hypertension. It is important to note that this definition is independent of admission arterial pressure. In those patients where the data were available (n 61), admission systolic and diastolic arterial pressure values were grouped into stages 1 4 of the JNC V classification. 6 This classification makes no allowance for age because of the increasing evidence that increased arterial pressure is associated with complications in all age groups. (ii) Ischaemic heart disease, including angina and myocardial infarction, previous cerebrovascular disease, peripheral vascular disease and diabetes mellitus. The definition of a positive risk factor was based on the medical records, indicating it to be present, rather than based on treatment history indicating the disease. This was because patients suffering significant myocardial ischaemia, with a previous myocardial infarction or peripheral vascular disease may be receiving no cardiovascular medication. The term diabetes mellitus includes patients treated with oral hypoglycaemic drugs, insulin or diet alone (as patients treated by the latter may also show significant end-organ damage). (iii) Renal impairment. Patients were said to have renal impairment if serum creatinine concentration was 150 µmol litre 1 on admission to hospital. Where no value was reported and there was no reference in the case notes to renal disease, patients were deemed not to have renal impairment. Data handling A computer database was written using Microsoft Access 2.0 to store and examine the data. Microsoft Excel (version 5.0) was used to examine the tables produced by Access. Statistical analysis was performed using Stata (version 4.0). Data were exchanged between the various programs using DBMScopy (version 5.10). Statistical tests For matched data, crude odds ratios were calculated as the ratio of the discordant pairs. 7 Paired Students t tests were used to compare admission systolic and diastolic arterial pressures of cases and controls. Multivariate analysis was performed using conditional logistic regression analysis. 8 This yielded a regression equation giving the effect of each risk factor after adjustment for the effect of other factors included in the equation. Where a risk factor was classified into a number of strata (as with arterial pressure), one of the stratum was taken as baseline. Thus admission arterial pressure was divided into three strata. Normal arterial pressure was taken as baseline and odds ratios are given for the two remaining strata compared with baseline. For the present analysis, systolic and diastolic arterial pressures were classified as normal (systolic pressure 140 mm Hg; diastolic pressure 90 mm Hg), moderately increased (stage 1 or 2 hypertension using the JNC V classification) or severely increased (stage 3 or 4 hypertension using the JNC V classification). Terms which were statistically significant at the 5% level using the log likelihood test were included in the final regression equation. Terms which did not achieve statistical significance were included if their inclusion had an impact on the coefficients of terms which were significant. We aimed, therefore to produce the most comprehensive model possible within the constraints of the data and for this reason terms with a relatively small confounding effect 680

3 Risk factors for cardiovascular death were included. Adjustments for sex and age differences within pairs were made irrespective of their impact. We also examined the data using the Wald test for each of the terms included in the final regression equation. 9 This test is performed by dividing the log odds ratio obtained from the regression model by its standard error to obtain a standard normal deviate. The P value is obtained using a table of probabilities. Because subjects were matched for age over a wide interval ( 10 yr), there was potential for residual confounding by age within pairs. A 10-yr age difference can have a considerable impact on risk, especially in elderly patients. Because of this, a term for within-pair age difference in years was included in the model. For a given pair of subjects, the impact of age difference was calculated by multiplying the coefficient for age obtained from the conditional logistic regression model by the difference in age between the case and control. This gives an odds ratio for the effect of within-pair age difference. In terms of the odds ratio, this is equivalent to raising the odds ratio to the power of the age difference in years (either positive or negative) and then multiplying the odds of death by this quantity. This provides a useful statistical correction for within-pair age difference. It does not give a direct description of the impact of age on perioperative risk. For both the crude and age-adjusted odds ratios, the 95% confidence limits are approximate and were obtained by conditional logistic regression. Results We initially identified 202 patients in the ORLS who were coded as emergency admissions and who died from a cardiovascular cause. A total of 128 were excluded for the following reasons: 34 underwent surgery under local anaesthesia; 24 were admitted as emergencies but underwent initial medical treatment and then later surgery; and 25 were excluded because their notes were untraceable (n 10) or there were no suitable controls. Forty-five patients did not fulfil the study criteria because 18 were found on case-note review to have had a pulmonary embolus, three had non-cardiovascular main causes of death and 24 were incorrectly coded. In the remaining case, death occurred before the patient reached the operating theatre. Seventy-three cases fulfilling the criteria of the study were identified in the ORLS coded as dying from a cardiovascular cause within 30 days of urgent or emergency surgery carried out under general anaesthesia. For the purpose of this study, urgent surgery was defined as within 48 h of admission, and without any change to the patient s normal treatment or introduction of any new treatment having taken place. Patients underwent general (n 20), vascular (n 9) or orthopaedic trauma surgical procedures, each matched with an appropriate control. Thirty-one (42%) of the cases and 27 (37%) of the controls were male. Mean age of the cases was 80.7 (range Table 1 Results for individual risk factors: concordant and discordant pairs. CVA Cerebrovascular accident; DM diabetes mellitus; HF heart failure; HT hypertension; MCI past history of myocardial infarction; RF renal impairment (plasma creatinine 150 µmol litre 1 ). Present, 0 absent. In the case of sex, male Case / Case / Case0/ Case0/ Control Control0 Control Control0 Angina CVA DM HF HT MCI RF Sex Table 2 Cardiovascular medications in the cases and controls (n) Cases α-methyl DOPA 5 0 ACE inhibitors 5 0 β-adrenoceptor blockers 5 1 Calcium entry blockers 6 2 Diuretics Nitrates 5 4 Aspirin 3 0 Digoxin 14 5 Controls ) yr and that of the controls, 80.8 ( ) yr. The time from anaesthesia and surgical operation to death ranged from 1 to 30 days (median 6; mode 2 days). Death was a result of an unspecified cause of cardiac arrest in six patients, myocardial infarction or ischaemic heart disease in 34 patients, heart failure in 16 patients and cerebrovascular accident in another 14 cases. In the remaining three patients, the causes of death were combined heart and renal failure, left ventricular hypertrophy and cardiomegaly, and valvular heart disease. The number of preoperative concordant and discordant pairs for each of eight risk factors are shown in Table 1 and the numbers of cases and controls receiving cardiovascular medication for hypertension, ischaemic heart disease, arrhythmia or congestive cardiac failure are shown in Table 2. The crude odds ratios for perioperative death for each of the risk factors are shown in Table 3, together with the odds ratios adjusted for residual confounding by age difference and sex within pairs. Neither the crude nor the age- and sex-adjusted odds ratios for hypertension were statistically significant. Among the other risk factors examined, the crude odds ratios were significant for heart failure and cerebrovascular accident. The strongest associations were seen for a history of heart failure, with a crude odds ratio of 11.0 (95% CI ; P 0.001) and cerebrovascular accident, where the odds ratio was 2.8 ( ; P 0.048). After adjustment for residual confounding by age, both of these risk factors remained statistically significant (Table 3). The associations between these various potential risk 681

4 Howell et al. Table 3 Results for individual risk factors. Data shown as crude and ageadjusted odds ratios. For both the crude and age-adjusted odds ratios, the confidence limits (CL) are approximate and were obtained by conditional logistic regression. (Abbreviations as in Table 1.) *z 3.258, P (using the Wald test); z 2.002, P (using the Wald test); age-adjusted Crude odds ratio (CL) Age and sex-adjusted odds ratio (CL) Angina 2.60 ( ) 2.60 ( ) CVA 2.80 ( ) 2.85 ( ) DM 0.67 ( ) 0.67 ( ) HF ( ) ( )* HT 1.27 ( ) 1.28 ( ) MCI 2.33 ( ) 2.44 ( ) RF 2.00 ( ) 1.92 ( ) Sex 1.31 ( ) 1.11 ( ) Table 4 Final conditional logistic regression model for risk factors for cardiovascular death after anaesthesia and urgent or emergency surgery (abbreviations as in Table 1), based on all 73 pairs. Data are odds ratio (mean (95% confidence intervals)). z values are based on the Wald test and associated P values Odds ratio (95% CI) z P Angina 1.63 ( ) CVA 3.50 ( ) HF ( ) HT 0.48 ( ) MCI 1.10 ( ) RF 2.96 ( ) Sex 0.86 ( ) Age difference 0.96 ( ) factors and postoperative cardiovascular death were then examined using conditional logistic regression analysis. The results are shown in Table 4. There was no significant effect of a history of hypertension, diabetes mellitus, ischaemic heart disease or a previous cerebrovascular accident. However, the adjusted odds ratio for a history of congestive heart failure was (95% CI ), which was significant by the Wald test (z 2.962; P 0.003). The term for diabetes mellitus was excluded from the final model as it had no significant main effect and little confounding effect. As in our previous study, 2 several patients collapsed and died suddenly, and while their deaths were attributed to myocardial infarction or arrhythmia, pulmonary embolism could not be excluded. Therefore, the dataset was reanalysed after exclusion of these patients. In this analysis, there were no significant changes in the coefficients for the other variables in the model. In a subgroup of 61 case-control pairs, admission preoperative arterial pressure data were also available. Mean admission systolic arterial pressure of the cases was (SD 29.2) mm Hg, and that of the controls, (25.4) mm Hg. The mean within-pair difference was 10.4 (35.6) mm Hg, and this was significant (t 2.27; P 0.027). Mean admission diastolic arterial pressure of the cases was 80.0 (14.6) mm Hg, and that of the controls, 85.4 (14.0) mm Hg. The mean within-pair difference was 5.5 (14.0) mm Hg, and this was significant (t 2.13; P 0.038). Table 5 Influence of arterial pressure on the final conditional logistic regression model of risk factors for cardiovascular death after urgent or emergency surgery based on 61 pairs of data. The regression coefficient (r) is the natural logarithm of the odds ratio (OR) for the risk factor in question. Each risk factor is coded as 1 present or 0 absent, except for age difference for which the absolute value in years is used, and sex, where male 1 and female 0. HT Hypertension r (SEM) OR (95% CI) z P Hypertension 0.03 (0.63) 1.0 ( ) Systolic HT Stages 1 and (0.59) 0.4 ( ) Stages 3 and (0.85) 0.5 ( ) Diastolic HT Stages 1 and (0.54) 1.1 ( ) Stages 3 and (1.20) 0.4 ( ) Heart failure 2.19 (0.93) 9.0 ( ) Renal impairment 1.52 (0.76) 4.6 ( ) Sex 0.36 (0.52) 0.7 ( ) Age difference 0.07 (0.06) 0.9 ( ) To assess the impact of treatment of arterial pressure, matching of pairs was broken and systolic and diastolic pressures of patients who received treatment for hypertension and those who did not were compared. Mean systolic pressure of patients receiving antihypertensive treatment was (30.2) mm Hg compared with (29.3) mm Hg for those not receiving treatment, and the corresponding diastolic pressures were 87.9 (14.1) mm Hg and 81.0 (15.9) mm Hg, respectively. These data were examined further by conditional logistic regression analysis to produce a model including terms for systolic and diastolic arterial pressures stratified as discussed earlier, heart failure, sex and within-pair age difference (Table 5). The adjusted odds ratio for heart failure was 9.0 (95% CI ; z 2.35; P 0.019). The term for withinpair age difference was not significant, and made little difference to the coefficients of the final model. It was felt appropriate to retain it because of the considerable withinpair age difference in some of the case-control pairs. The term for hypertension was not statistically significant (z 0.05; P 0.96). On likelihood ratio testing, inclusion of terms for systolic and diastolic pressures (chi-square 2.33 (2 df), P 0.31; and chi-square 0.57 (2 df), P 0.75, respectively) did not statistically improve the model. Discussion A recent CEPOD report found an incidence of deaths caused solely by anaesthesia of 1 in operations, while anaesthesia was partially responsible for 1 in 1354 deaths. 10 In a retrospective study of patients from Cardiff, Fowkes and colleagues found mortalities of 1.5 per 100 elective patients and 5.3 per 100 emergency cases. 3 Pederson and Johansen showed comparable incidences of overall postoperative complications after both types of anaesthesia and surgery in 7306 patients, but a greater incidence of serious outcomes (myocardial infarction, brain damage and death) in emergency patients (0.16% vs 0.04%). 11 In the multicentre study of Forrest and colleagues, 12 serious outcome, including death, was observed in 847 of patients (4.9%). Step- 682

5 Risk factors for cardiovascular death wise logistic regression analysis identified several major risk factors history of cardiac failure, myocardial ischaemia and infarction, hypertension, or age greater than 55 yr. Congestive cardiac failure was also defined as a major contributor to morbidity and mortality in the studies of Farrow and colleagues 13 and Tuman and colleagues. 14 In another study by Wolters and colleagues, 15 examining ASA classification as a predictor of postoperative outcome, they identified several risk factors during either elective or emergency surgery. There was a significant association between ASA status and postoperative mortality, as demonstrated previously by other authors. 316 Other factors leading to an increased rate of postoperative complications included renal insufficiency (serum creatinine 1.5 mg dl 1 (130 µmol litre 1 )), anaemia (Hb 10 g dl 1 ), bronchopulmonary disease, history of smoking and old age. Using logistic regression analysis, Wolters and colleagues found an increased odds ratio for any postoperative complication (including death in hospital) after emergency surgery of 1.24 (95% CI ). 15 Similar increased odds ratios after emergency surgery were found by Tiret and colleagues 17 for postoperative complications (odds ratio 2.0); by Pederson and Johansen 11 for the risk of needing postoperative assisted ventilation (odds ratio 2.1); and death within 7 days of surgery (odds ratio 4.4). 18 In our study, we found a strong association between a history of heart failure and perioperative cardiovascular death. The inverse association between admission arterial pressure and outcome may reflect the occurrence of hypotension in acutely unwell patients admitted to hospital. 19 Among possible causes of this low arterial pressure are blood loss and fluid depletion as a result of third space losses or vomiting, or because of under-resuscitation. In all of these circumstances, it is reasonable to expect the relative hypotension to be associated with increased risk. In both the APACHE II and APACHE III scoring systems, the presence of hypotension increases the score and so the likelihood of an adverse outcome More than 50% of the patients in our study underwent surgery for fractured neck of femur. A recent study by Sinclair, James and Singer has suggested that routine fluid rehydration (based on crystalloid alone) results in patients being under resuscitated. 22 Such patients may have a lower preoperative arterial pressure and be more vulnerable to perioperative cardiovascular complications. Such an effect may not be confined to patients who have suffered fractured neck of femur. 23 Regression analysis of our data including a term fractured neck of femur vs other operation, and seeking both a main effect of the operation and any relevant interactions, did not show patients who underwent surgery for hip fracture to behave differently with respect to outcome compared with those undergoing other operative procedures. Although there were differences between admission arterial pressures of the cases and controls, no association between arterial pressure and outcome was found after the effect of other confounding variables had been taken into account. It may be that in the surgical population, patients with moderate or severe heart failure sufficient to increase the perioperative cardiovascular risk tend to have lower systolic arterial pressures. In an evaluation of the cardiac predictors of death after noncardiac emergency surgery, Dirksen and Kjoller 24 studied 320 patients undergoing appendicectomy or hip fracture surgery, and who had suffered a previous myocardial infarction. They found that a past history of congestive cardiac failure either before or during admission for myocardial infarction was the dominant risk factor (odds ratios 3.10). Congestive cardiac failure with pulmonary congestion, a past history of heart failure or peripheral cardiac oedema is seen in approximately 3 9% of all anaesthetized patients undergoing non-cardiac surgery. Both Larsen and colleagues 25 and Pederson, Eliasen and Henriksen 26 found these patients to show high incidences of postoperative cardiac complications and death. Pederson, Eliasen and Henriksen 26 found that the presence of heart failure and myocardial infarction within the previous year were major determinants of intra- and postoperative cardiovascular complications, but that only chronic heart failure was of major importance for in-hospital death. The highest incidence of postoperative cardiovascular complications (42%) and death after anaesthesia and surgery (22%) was found in emergency cases where preoperative arterial pressure was 90 mm Hg. 26 Renal impairment was also a risk factor for perioperative cardiovascular death in the emergency patient. Apart from underlying renal pathology, this may also represent the effects of under-resuscitation, sepsis or circulatory failure, all of which may increase the risk of mortality. Patients with renal impairment are at increased risk of ischaemic heart disease and are therefore more likely to be at increased risk of perioperative ischaemia. Their anaesthetic management may also present a considerable challenge because of altered drug handling and difficulties with fluid and electrolyte balance. Plasma creatinine concentration increases with age. The value we arbitrarily chose in this study (150 µmol litre 1 ) was the upper limit of the reported normal range, but this may be regarded as too low in the relatively elderly population included in our study. However, re-analysis of the data using an upper limit of 200 µmol litre 1 did not affect the result. The association between cerebrovascular accident (CVA) and cardiovascular death was identified by univariate analysis but not confirmed by multivariate analysis. A history of cerebrovascular disease may increase the risk of perioperative stroke, and may be a marker of other, more widespread, cardiovascular disease. Failure of this risk factor to achieve significance in the final model may have been because of a lack of statistical power, as reflected in the wide confidence intervals in Table 4. Many of the limitations of the method of analysis cited in our previous article apply to this study. 2 In the present study, the matching criteria were loosened, but this still resulted in 15 cases being unmatchable. In contrast with the elective study, sex was included in the analysis rather than being 683

6 Howell et al. controlled for by matching. However, there was no main effect of sex, although it was retained within the model to allow the reader to make comparisons with our elective surgery patients. 2 Concerns about the accuracy of the diagnoses entered on death certificates are relevant. As patients underwent urgent or emergency surgery, there was less likelihood of anaesthetists cancelling operations through poorly controlled hypertension. There were, however sufficient patients with increased arterial pressure to allow examination of this risk factor, as 25% of the cases had systolic pressures 170 mm Hg and a diastolic pressure 95 mm Hg. The final conditional regression model may suffer from a lack of statistical power, as ideally there should be at least 10 subjects who suffered an adverse outcome for each variable included in the model. There were nine coefficients in the final equation and their inclusion can be justified either on the grounds of clinical relevance or, in the case of age difference and sex, as necessary adjustments for confounding. In summary, we identified a history of congestive cardiac failure as the main risk factor for postoperative cardiovascular death in patients who underwent emergency or urgent surgery. There was no clear association between hypertension and perioperative cardiovascular mortality, and there was no evidence that increased admission arterial pressure was associated with adverse outcome. In contrast, patients who suffered adverse outcomes (cases) tended to have lower admission arterial pressures than controls. The low statistical power of some of the risk factors in the final equation (Table 4; namely cerebrovascular accident and renal impairment) may have contributed to their lack of significance. Comparison of this study with our previous elective surgical patients indicate that the two patient groups may have had different cardiovascular risk profiles. This may be because patients are at greater risk from their presenting condition than of any cardiovascular co-morbidity. By the same token, cardiovascular changes caused by the presenting condition may be more important than any effect of premorbid increase in arterial pressure. Acknowledgements The Oxford Record Linkage Study (ORLS) is funded by the Anglia and Oxford Regional Health Authority (AORHA). S. J. H. was funded for part of the period of this study by the AORHA. References 1 Howell SJ, Sear YM, Yeates D, Goldacre M, Sear JW, Foex P. Hypertension, admission blood pressure and perioperative cardiovascular risk. Anaesthesia 1996; 51: Howell SJ, Sear YM, Yeates D, Goldacre M, Sear JW, Foex P. Risk factors for cardiovascular death after elective surgery under general anaesthesia. 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