Background Elevation of systemic oxygen delivery and consumptionhas been associated with an improved outcome in critically illpatients. We conducted a randomized trial to determine whetherboosting oxygen delivery by infusing the inotropic agent dobutaminewould improve the outcome in a diverse group of such patients.
Methods On the basis of previously published recommendations,we established the following goals: a cardiac index above 4.5liters per minute per square meter of body-surface area, oxygendelivery above 600 ml per minute per square meter, and oxygenconsumption above 170 ml per minute per square meter. If thesegoals were not achieved with volume expansion alone, patientswere randomly assigned to a treatment or control group. Thetreatment group received intravenous dobutamine (5 to 200 µgper kilogram of body weight per minute) until all three goalshad been achieved. Dobutamine was administered to the controlgroup only if the cardiac index was below 2.8 liters per minuteper square meter.
Results A total of 109 patients were studied. In nine patientsthe therapeutic goals were achieved with volume expansion alone;all nine patients survived to leave the hospital. Fifty patientswere randomly assigned to the treatment group, and 50 to thecontrol group. During treatment, there were no differences betweenthe two groups in mean arterial pressure or oxygen consumption,despite a significantly higher cardiac index and level of oxygendelivery in the treatment group (P<0.05). Although the predictedrisk of death during hospitalization was 34 percent for bothgroups, the in-hospital mortality was lower in the control group(34 percent) than in the treatment group (54 percent) (P = 0.04;95 percent confidence interval, 0.9 to 39.1 percent).
Conclusions The use of dobutamine to boost the cardiac indexand systemic oxygen delivery failed to improve the outcome inthis heterogeneous group of critically ill patients. Contraryto what might have been expected, our results suggest that insome cases aggressive efforts to increase oxygen consumptionmay have been detrimental. .
Despite improvements in resuscitation and supportive care, oneor more vital organs fail in a large proportion of patientswith acute, life-threatening illnesses1. It has been proposedthat organ damage in critical illness is due to inadequate oxygendelivery, often exacerbated by a level of tissue oxygen extractionthat fails to satisfy metabolic demands2. Consequently, someinvestigators have recommended that in patients at high riskwho are undergoing surgery, the cardiac index and the deliveryand consumption of oxygen be increased to levels that have previouslybeen identified as the median maximal values in survivors (cardiacindex, over 4.5 liters per minute per square meter of body-surfacearea; oxygen delivery, over 600 ml per minute per square meter;and oxygen consumption, over 170 ml per minute per square meter)to replenish tissue oxygen and prevent organ dysfunction3,4,5.One study demonstrated a marked reduction in mortality amongpostoperative patients at high risk who were treated in thisway,5 and more recent studies have supported the idea that anelevation of oxygen delivery to levels that some have called"supranormal" improves the outcome in patients with trauma6and septic shock,7,8,9 as well as in heterogeneous groups ofcritically ill patients10.
Some researchers, however, remain skeptical11. Provided volumereplacement is optimal, it remains unclear whether achievementof these target values simply indicates an adequate physiologicreserve and therefore a better outcome. Although the prognosisis very good for patients in whom oxygen delivery and consumptionreach the target levels in response to intravenous fluids aloneor only moderate inotropic support, in a substantial numberof patients it proves impossible to increase oxygen consumptiondespite aggressive inotropic support12. In such patients theoutcome is poor,12 and the use of high doses of inotropic agentsmay be associated with an increased incidence of complications,such as tachyarrhythmias, myocardial ischemia, and maldistributionof tissue blood flow. Furthermore, inotropic support is frequentlynot started until the patient has been admitted to the intensivecare unit, and then it is not clear whether boosting oxygendelivery can improve the outcome.
We carried out a prospective, randomized, controlled study ofa heterogeneous group of critically ill patients. The purposeof the study was to examine the effects of treatment intendedto increase the cardiac index and oxygen delivery and consumptionto the previously reported median values in survivors. Treatmentwas initiated at the time of admission to intensive care.
Methods
The study was reviewed and approved by the ethics committeeof the participating hospitals. The patients were unable togive informed consent because of the severity of their condition.Informed consent was therefore obtained from each patient'sclosest relative.
Selection and Randomization of Patients
Consecutive patients at high risk who were admitted to the intensivecare units at two hospitals over a two-year period were screenedfor inclusion in the study. For patients undergoing surgery,the criteria for high risk were taken from Shoemaker et al.5.Patients not undergoing surgery who had life-threatening cardiorespiratoryillnesses (acute respiratory failure or septic shock) were alsoincluded. Patients were excluded if they were less than 16 yearsof age, pregnant, or undergoing neurosurgery or if they hadpreexisting cardiac disease or hematologic cancer.
After fluid resuscitation, patients in whom the cardiac indexand oxygen consumption and delivery failed to reach the targetvalues (see below) were randomly assigned to the treatment orcontrol group with the use of a table of random numbers.
Classification of Condition
Patients were classified as having the sepsis syndrome or septicshock if they met the criteria described by Bone et al.,13 andthe adult respiratory distress syndrome if they met the followingcriteria: a compatible underlying clinical disorder, an inspiredoxygen fraction over 0.4 required to maintain the partial pressureof arterial oxygen at a value over 60 mm Hg, radiologic evidenceof diffuse bilateral pulmonary infiltrates, and pulmonary-arteryocclusion pressure under 18 mm Hg. Admission diagnoses wereclassified according to the system of Knaus et al.14.
Management
On admission to the intensive care unit, all patients underwenturinary, peripheral arterial, central venous, and pulmonaryarterial catheterization. Dopamine was administered to all patientsat a dose of 2 µg per kilogram of body weight per minute.Saturation of arterial blood with oxygen was maintained at alevel over 90 percent. Intravenous fluids were administeredas necessary to achieve an optimal left atrial filling pressure.(The optimal value was determined by plotting the left ventricularstroke-work index against the pulmonary-artery occlusion pressure,with the optimal filling pressure defined as the pulmonary-arteryocclusion pressure at the plateau value for left ventricularstroke work.) Blood, human albumin solution, or synthetic colloidswere infused as necessary while the hemoglobin concentrationwas maintained at a level higher than 10 g per deciliter.
Patients were not assigned to the treatment or control groupif all three goals (cardiac index above 4.5 liters per minuteper square meter of body-surface area, oxygen delivery above600 ml per minute per square meter, and oxygen consumption above170 ml per minute per square meter) were achieved after volumeexpansion. Patients in whom these goals were not achieved wererandomly assigned to either the treatment group or the controlgroup.
In the treatment group dobutamine (5 to 200 µg per kilogramper minute) was administered to increase the cardiac index andoxygen delivery until all three goals had been achieved simultaneously,unless there was sinus tachycardia at a rate over 130 beatsper minute, tachyarrhythmia, or electrocardiographic evidenceof myocardial ischemia, in which case the dose of dobutaminewas immediately decreased or discontinued and then titratedto achieve the highest possible values for the cardiac indexand oxygen delivery and consumption. In the control group dobutaminewas administered only if the cardiac index was less than 2.8liters per minute per square meter.
In all groups norepinephrine (0.05 to 20 µg per kilogramper minute) was administered, if required, to maintain the meanarterial pressure at 80 mm Hg while avoiding excessive peripheralvasoconstriction (systemic-vascular-resistance index above 1500dyn • sec • cm-5 per square meter). In both groupstreatment was initiated in the intensive care unit, the aimbeing to achieve target values as soon as possible after enrollment,and was continued until death or apparent resolution of theacute illness.
Measurements
Cardiac output was measured by thermodilution. Hemoglobin andoxygen saturation were determined with a blood oximeter (Cooximeter282, Instrumentation Laboratories, Lexington, Mass.). Arterialblood lactate levels were measured by an enzymatic technique(GM7 microstat, Analox Instruments, London). The cardiac index,systemic-vascular-resistance index, left ventricular stroke-workindex, and oxygen delivery and consumption were calculated withthe use of standard formulas. The oxygen-extraction ratio (ameasure of the efficiency of tissue oxygen uptake) was calculatedas the difference between arterial and venous oxygen content,divided by the arterial oxygen content.
All measurements were obtained on patients' admission to thestudy; after optimal volume administration; at 1, 2, 4, 8, 12,16, 20, and 24 hours; every 6 hours for the next 24 hours; andthen at least every 8 hours. Scores for the Acute Physiologyand Chronic Health Evaluation (APACHE) II14 and APACHE III15and for organ failure16 were determined with the use of a specificintensive-care data base (Acubase, Clinical Information Systems,Seattle). The risk of death for each patient was predicted fromthe APACHE II score with the use of the regression equationand with the diagnostic category weighted according to the systemof Knaus et al.14.
Statistical Analysis
Data are presented as medians and ranges or as medians ±the25th and 75th percentiles of the ranges. The incremental areaunder the curve was used as a summary statistic for the measurementsfor each patient17 to compare the cardiac index, oxygen deliveryand consumption, oxygen-extraction ratio, lactate concentration,and mean arterial pressure in the treatment and control groupsfor the 48-hour period after optimal volume expansion. If apatient died or was discharged from the intensive care unitbefore the end of that period, the last set of values obtainedbefore death or discharge was used. At 48 hours, 7 of the 50patients in the control group and 10 of the 50 in the treatmentgroup had died or been discharged from intensive care.
Comparisons between groups were performed with the Mann-WhitneyU test. Discrete data were analyzed with the chi-square test.Mortality data are presented with 95 percent confidence intervals.Differences were considered significant when the probabilitythat they were due to chance was less than 0.05. All P valuesare two-sided.
Before starting the study, we calculated that with a power of80 percent and a significance level of 5 percent, 130 patientswould be required in each group to demonstrate a 15-percentage-pointreduction in the mortality rate (from the expected rate of 33percent to 18 percent). An interim analysis of outcome in thehospital was scheduled after randomization of each block of50 patients. At the second interim analysis, in-unit mortalityand in-hospital mortality were unexpectedly higher in the treatmentgroup than in the control group. Moreover, actual mortalitywas higher than predicted mortality in the treatment group,whereas in the control group actual and predicted mortalitywere the same. Because our best estimate at the time was thatthe treatment protocol was diminishing survival and the 95 percentconfidence intervals indicated that there was unlikely to besubstantial advantage for the patients in the treatment group,we decided to discontinue the study18. The data presented hereare for the 100 patients randomly assigned to the treatmentor control group before the study was discontinued.
Results
We studied a total of 109 patients (69 men and 40 women). Innine patients the therapeutic goals were achieved with fluidadministration alone, and these nine were therefore not randomlyassigned to the treatment or control group. A total of 50 patientswere randomly assigned to the control group, and 50 to the treatmentgroup. Characteristics of the patients at the time of admissionare shown in Table 1. There were no significant differencesin age, APACHE II or III score, predicted risk of death, ororgan-failure score between the control and treatment groups(Table 1 and Table 2).
Hemodynamic Data, Oxygen Delivery and Consumption, and Lactate Levels
The 48-hour incremental area under the curve for cardiac index(Figure 1) and oxygen delivery (Figure 2) was significantlyhigher in the treatment group than in the control group (P<0.001and P = 0.0012, respectively). In the treatment group, however,the increase in the cardiac index and oxygen delivery was accompaniedby a fall in the oxygen-extraction ratio. As a result, the 48-hourincremental area under the curve for the oxygen-extraction ratiowas significantly lower in the treatment group than in the controlgroup (P = 0.045), and the difference in oxygen consumptionbetween the two groups was not significant (P = 0.12) (Figure 3).The 48-hour incremental area under the curve for mean arterialpressure and lactate level also did not differ significantlybetween the two groups (P = 0.42 and P = 0.34, respectively).
Figure 1. Median Cardiac Index in the Treatment and Control Groups.
The 25th and 75th percentiles of the range are shown at base line and 12, 24, 48, and 72 hours after optimal volume replacement (t1). Solid circles denote the treatment group, and open circles the control group. The horizontal line indicates the target value for the treatment group. P<0.001 for the comparison between the two groups in the incremental area under the curve (for the first 48 hours after optimal volume replacement).
Figure 2. Median Oxygen Delivery in the Treatment and Control Groups.
The 25th and 75th percentiles of the range are shown at base line and 12, 24, 48, and 72 hours after optimal volume replacement (t1). Solid circles denote the treatment group, and open circles the control group. The horizontal line indicates the target value for the treatment group. P = 0.0012 for the comparison between the two groups in the incremental area under the curve (for the first 48 hours after optimal volume replacement).
Figure 3. Median Oxygen Consumption in the Treatment and Control Groups.
The 25th and 75th percentiles of the range are shown at base line and 12, 24, 48, and 72 hours after optimal volume replacement (t1). Solid circles denote the treatment group, and open circles the control group. The horizontal line indicates the target value for the treatment group. P = 0.12 for the comparison between the two groups in the incremental area under the curve (for the first 48 hours after optimal volume replacement).
There was no significant difference in lactate levels (median±25th and 75th percentile) between the two groups eitherinitially (treatment group, 2.2 ±1.8 and 3.5 mmol perliter; control group, 2.1 ±1.5 and 3.3 mmol per liter;P = 0.69) or at 48 hours (treatment group, 1.7 ±1.23and 2.5 mmol per liter; control group, 1.5 ±1.1 and 2.1mmol per liter; P = 0.2). In both groups lactate levels at 48hours were significantly lower than base-line values (P<0.05).
Use of Inotropic and Vasoactive Agents
Thirty-four patients in the control group and 31 in the treatmentgroup received norepinephrine. The median maximal dose administeredin the control group was 0.23 µg per kilogram of bodyweight per minute (range, 0.05 to 10), which was significantlylower than that administered in the treatment group (1.2 µgper kilogram per minute [range, 0.02 to 16.6]) (P = 0.029).
Twenty-one patients in the control group and all the patientsin the treatment group received dobutamine at some time duringthe study. The median maximal dose administered in the controlgroup was 10 µg per kilogram per minute (range, 2.5 to200), which was significantly lower than that administered inthe treatment group (25 µg per kilogram per minute [range,2.5 to 200]) (P<0.001). Seventeen patients in the treatmentgroup received 50 µg or more of dobutamine per kilogramper minute at some time during the study.
In 35 of the 50 patients in the treatment group, the three targetvalues were not achieved simultaneously despite inotropic support.The in-hospital mortality in this group was 71 percent (themedian predicted risk of death was 42 percent [range, 3 to 85percent]). Dose increments were limited by complications in24 patients in the treatment group. Twelve patients had tachycardiaat a rate above 130 beats per minute despite the maintenanceof an optimal pulmonary-artery occlusion pressure, eight hadelectrocardiographic signs of ischemia, five became hypertensive,and two had tachyarrhythmias.
Outcome
All nine patients in whom the therapeutic goals were achievedwith volume expansion alone survived to leave the hospital.The treatment and control groups did not differ significantlyin the number of days of ventilation, the length of stay inthe intensive care unit, or the time spent in the hospital.At the second interim analysis, both in-unit and in-hospitalmortality were higher (P = 0.04) in the treatment group thanin the control group (Table 2). In-unit mortality was 30 percentin the control group as compared with 50 percent in the treatmentgroup (95 percent confidence interval, 1.2 to 38.8 percent).In-hospital mortality was 34 percent (the same as the predictedrisk of death) in the control group as compared with 54 percent(predicted risk of death, 34 percent) in the treatment group(95 percent confidence interval, 0.9 to 39.1 percent) (Table 2and Figure 4). The proportion of deaths due to intractablehypotension and cardiac events was similar in the two groups.The excess deaths in the treatment group occurred later andwere attributable to multiple organ failure (Table 2 and Figure 4).
Figure 4. In-Hospital Survival of Patients in the Treatment and Control Groups.
In-hospital mortality in the subgroup of patients with septicshock was 52 percent (predicted risk of death, 60 percent) inthe control group as compared with 71 percent (predicted riskof death, 51 percent) in the treatment group. In-hospital mortalityin the subgroup of patients with the adult respiratory distresssyndrome was 67 percent (predicted risk of death, 53 percent)in the control group as compared with 81 percent (predictedrisk of death, 47 percent) in the treatment group. Neither ofthese subgroup differences was significant.
Discussion
In this prospective, randomized, controlled study of criticallyill patients, treatment with intravenous dobutamine that wasintended to increase the cardiac index and oxygen delivery andconsumption to previously recommended levels did not improvethe outcome. With the use of precise guidelines for treatment,oxygen delivery was successfully increased and maintained abovethe target level in the treatment group, but this increase wasassociated with a fall in oxygen extraction. As a result, therewas no difference in oxygen consumption between the two groups,despite significantly higher values for the cardiac index andoxygen delivery in the treatment group. These findings are consistentwith data recently reported in patients with septic shock9 andin a mixed group of critically ill patients10. In an earlierstudy of patients undergoing surgery, however, oxygen consumptionwas higher in the treatment group than in the control group,and mortality was reduced from 33 percent to 4 percent,5 suggestingthat the increase in oxygen consumption in response to enhancedoxygen delivery may have been associated with the reversal oftissue hypoxia, the prevention of organ failure, and a consequentreduction in mortality. In a similar investigation of patientswith trauma,6 oxygen consumption was increased in the treatmentgroup and there was a trend toward a reduction in mortality,although it was not significant. In a study of high-risk patientsundergoing surgery, treatment aimed at achieving a level ofoxygen delivery higher than 600 ml per minute per square meter,instituted preoperatively (in most of the patients) or in theearly postoperative period, reduced the 28-day mortality rateby 75 percent, although the elevation in oxygen delivery wasmodest and there was no increase in oxygen consumption19. Theresults of this study may also have been influenced by the useof dopexamine instead of dobutamine to increase oxygen delivery.Edwards et al. reported that the use of dobutamine and norepinephrineto achieve target levels for the cardiac index and oxygen deliverywas associated with an increase in oxygen consumption and mayhave improved the outcome in patients with septic shock,7 althoughthis finding was based on comparisons with historical controls.
The contrast between our results and those reported in previousstudies5,19 may be due to differences in the patient populations,as well as in the timing of therapy and the doses of inotropicagents used. Although our patients were a heterogeneous group,the majority had undergone surgery and were typical of patientsadmitted to general intensive care units; most had the sepsissyndrome, septic shock, the adult respiratory distress syndrome,or a combination of these conditions. In the studies reportedby Shoemaker et al.5 and Boyd et al.,19 all the patients hadundergone surgery, and treatment was usually instituted preoperatively,whereas in our study pulmonary-artery flotation catheters wereinserted after patients were admitted to the intensive careunit, almost always postoperatively, and often after complicationshad occurred on the ward. Mortality has previously been shownto be much higher in such circumstances,5 probably because itis difficult or impossible to reverse the cycle of events leadingto organ damage. The median APACHE II score in the study byBoyd et al. was 8,19 which is much lower than the median scoreof 18 in our study.
Unlike the protocol in other studies,5,6,10 an important featureof our investigation was that patients in whom the hemodynamicgoals were achieved with fluid administration alone were notrandomly assigned to the treatment or control group. Shoemakerand coworkers were successful in achieving the hemodynamic goalswith fluid administration alone in two thirds of their patients,20suggesting that the improved outcome in their study may havebeen largely related to more aggressive volume replacement.Although neither morbidity nor mortality was improved by theregimen used in our treatment group, it is important to notethat when all the patients in our study are considered, includingthe 9 who were not randomized, all but 2 of the 33 patientsin whom target values for the cardiac index and oxygen deliveryand consumption were achieved survived to leave the hospital.This supports the idea that the ability to achieve the desiredlevels of oxygen delivery and consumption indicates a largerphysiologic reserve, less severe illness, and consequently,a better prognosis.
It is unclear why the outcome was worse in the treatment group,since randomization resulted in well-matched groups and therewas no difference in mean arterial pressure between the groups.It is conceivable that the larger doses of dobutamine used inthe treatment group limited the rise in oxygen consumption byexacerbating the maldistribution of blood flow within the microcirculation,resulting in impaired perfusion of vital organs, such as thegastrointestinal tract, and thereby contributing to the higherincidence of multiple-organ failure in the treatment group.The larger doses of dobutamine administered to patients in thetreatment group may also explain the greater need for norepinephrinein this group, and the possibility that norepinephrine furtherexacerbated tissue ischemia cannot be excluded.
We conclude that when volume replacement was adequate and perfusionpressure well maintained, the overall outcome in high-risk patientswas not improved by using dobutamine at the time of admissionto the intensive care unit in an attempt to achieve target valuesfor oxygen delivery and consumption. Not only was it often impossibleto increase oxygen consumption, but our results also suggestthat in some cases aggressive efforts to boost oxygen consumptionmay have been detrimental. Further studies will be requiredto establish whether these results apply to homogeneous subgroupsof patients, such as those with trauma or septic shock, andwhether less aggressive treatment that is more precisely tailoredto an individual patient's requirements may be more effective.It remains to be seen whether there are advantages to targetingoxygen delivery rather than oxygen consumption and whether otherinotropic agents may have a more favorable effect on oxygenconsumption. The effect of preoperative rather than postoperativeinstitution of therapy in patients undergoing emergency surgeryand in those undergoing elective surgery also merits furtherinvestigation.
Supported by a grant from the North East Thames Regional HealthAuthority, administered through the Joint Research Board andMedical College, St. Bartholomew's Hospital. Dr. Yau is therecipient of an Aylwen bursary from the Medical College of St.Bartholomew's Hospital.
We are indebted to the nursing staff of the intensive care unitsat St. Bartholomew's Hospitals at Smithfield and Homerton fortheir enthusiasm and cooperation while this study was in progress,to the consultant staff at both institutions for permissionto study their patients, to Miss Janice Thomas for statisticaladvice, and to Dr. Cyril Vesey for measuring lactate concentrations.
Source Information
From the Departments of Anesthesia and Intensive Care, St. Bartholomew's Hospitals at Smithfield and Homerton (M.A.H., A.C.T., E.H.S.Y., C.J.H., D.W.), and the Departments of Anesthesia and Intensive Care, Charing Cross Hospital (M.P.) -- all in London.
Address reprint requests to Dr. Watson at the Department of Anesthesia, St. Bartholomew's Hospital at Smithfield, West Smithfield, London EC1A 7BE, United Kingdom.
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