Randomized controlled trial of interrupted versus continuous sedative infusions in ventilated children

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1 Feature Articles Randomized controlled trial of interrupted versus continuous sedative infusions in ventilated children Kunal Gupta, MD; Vipul K. Gupta, MD, DNB; Jayashree Muralindharan, MD; Sunit Singhi, MD Objective: To compare daily interruption vs. continuous sedative infusions in mechanically ventilated children with respect to lengths of mechanical ventilation and intensive care unit stay. Design: Prospective randomized controlled trial. Setting: Pediatric intensive care unit of a tertiary care teaching and referral hospital. Patients: One hundred two patients mechanically ventilated for >48 hrs. Interventions: Patients were randomized to receive either continuous (group 1) or interrupted (group 2) sedative infusion (midazolam bolus of 0.1 mg/kg, followed by infusion, to achieve a Ramsay score of 3 4). Each patient in group 2 had daily interruption of infusion at 8:00 AM till he/she became fully awake (response to verbal commands) or so agitated/uncomfortable that he/she needed restarting of infusion (whichever was earlier) at a dose 50% less than the previous dose. Primary outcome variables were the lengths of mechanical ventilation and intensive care unit stay, while the number and percentage of days awake on sedative infusions, frequency of adverse events, and total dose of sedatives required were the secondary outcome variables. Measurements and Main Results: Of the 102 patients included in the study, 56 were randomized into the continuous sedation protocol and 46 into the interrupted sedation protocol. Both were statistically similar with respect to demography, primary diagnosis, severity of illness score (Pediatric Risk of Mortality I and III), indication for mechanical ventilation, and initial ventilatory variables except that the patients under the interrupted arm had lower peak inspiratory pressure and positive end-expiratory pressure requirements at the start of ventilation (p.002 and p.028, respectively). The mean (SD) length of mechanical ventilation in the interrupted sedation protocol was significantly less than that in the continuous sedation protocol ( days vs days; p.021). Similarly, the difference in the median duration of pediatric intensive care unit stay was significantly less in the interrupted sedation as compared to the continuous sedation protocol (10.7 days vs days; p.048). The mean total dose of midazolam and the total calculated cost of midazolam in the former were significantly less compared to those of the latter ( ml vs ml, p.002; rupees vs. 13,865 25,338 rupees, p.020). The frequencies of adverse events in both the groups were however similar. Conclusion: The length of mechanical ventilation, duration of intensive care unit stay, total dose of midazolam, and average calculated cost of the therapy were significantly reduced in the interrupted as compared to the continuous group of sedation. (Pediatr Crit Care Med 2012; 13: ) KEY WORDS: sedation; interrupted; continuous; ventilation Sedation and analgesia are an integral part of intensive care, especially in children receiving mechanical ventilation (MV), as they reduce the stress response, provide anxiolysis, improve tolerance to ventilatory support, and facilitate nursing care (1 4). Unfortunately, sedation has the potential to prolong MV and intensive care unit (ICU) stay, thus increasing the healthcare costs (5). Hence, protocols aimed at minimizing the complications of cumulative sedation From the Department of Pediatrics, Postgraduate Institute of Medical Education and Research, Chandigarh, India. The authors have not disclosed any potential conflicts of interest. For information regarding this article, mjshree@hotmail.com Copyright 2012 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies DOI: /PCC.0b013e31820aba48 have been developed (1). In this regard, daily interruption of sedative infusions was found to be a better option, as it reduced the durations of MV and the hospital stay (6). There are very few randomized controlled trials addressing this issue, and those available pertain to adult ICU patients (6, 7). Extrapolating the findings of adult studies to the pediatric population would be inappropriate as children are difficult to restrain and nurse as compared to adults. The objective of this study therefore was to compare daily interruption vs. continuous administration of sedative infusions in mechanically ventilated children with respect to the lengths of MV and ICU stay, number and percentage of days awake on MV, frequency of adverse events, and dose and cost of midazolam required. MATERIALS AND METHODS The study was a prospective randomized controlled trial conducted in the pediatric intensive care unit (PICU) of a referral and teaching hospital in North India over a period of 1 yr from January 2007 to December We also included 32 patients from a pilot study conducted in the same unit with exactly the same methodology over a period of 1 yr from June 2004 to July This pilot study was also approved by the Institute s Ethics Committee. Informed written consent was obtained from the parents. Patients All patients admitted to the PICU and who were on MV for 48 hrs were eligible for consecutive enrollment into the study. Patients requiring a peak inspiratory pressure (PIP) of 28 mm Hg were excluded from the study. Demographic details, admission Pediatric Risk of Mortality scores, and indications for PICU admission were recorded in all at the time of enrollment. Interventions Patients were randomized into two groups after the eligibility for enrollment was ascer- 131

2 tained. Group 1 was assigned to the continuous infusion of sedative protocol and group 2 to the daily interruption of sedative infusion protocol. Intravenous midazolam was first given as a mg/kg bolus over 2 3 mins, followed by infusion of 0.1 mg/kg/hr, an increase to 0.3 mg/kg/hr, and titration to achieve a Ramsay score of 3 4 (8). This was combined with an opioid analgesic, morphine, given as an infusion in the dose of mg/kg/hr. Group 1 continued to receive the above protocol with interruption done as per the advice of the treating team, whenever it was needed, while group 2 patients had a daily interruption of sedative infusion at 8:00 AM. This interruption was continued until the patient became fully awake (with response to verbal commands) or became agitated and uncomfortable to such an extent that he/she needed to be restarted on infusion again (whichever was earlier) at a dose 50% less than the previous dose and titrated according to the need for sedation. All patients were monitored for wakefulness (if he/she responded to the verbal commands). The percentage of days on which the patient was awake (number of days awake divided by the total number of days during which sedative infusion was given) was recorded. Measures Primary. The total duration of MV and length of ICU stay were primary outcome variables. Secondary. The number and percentage of days awake on sedative infusions, frequency of adverse events, and total dose of sedatives with its equivalent cost were secondary outcome variables. Randomization Randomization by stratification was done at 48 hrs of ventilation by a faculty member who was not directly involved in the study by using computer-generated random numbers. This was done to distribute patients with neuromuscular illnesses into both groups evenly. The allocations were kept in sealed numbered envelopes. Each numbered envelope contained a slip showing 1 (for continuous sedation) or 2 (for interrupted sedation). The patient assignment was made by opening the numbered envelopes. The envelopes were opened only after written consent for enrollment was obtained. The participants and those administering the interventions were however not blinded to the group assignment. Sample Size Table 1. Baseline characteristics of study subjects Variable Assuming a failure rate of 30% in the continuous sedation group and a desired reduction of the failure rate to 10% in the interrupted sedation group, with an error of 5% and power of 80%, we calculated that approximately 47 subjects would be required in each group. Statistical Analysis All quantitative variables were analyzed using measures of central location (mean, median, and mode) and measures of dispersion (standard deviation and standard error). Their 95% confidence intervals (CIs) were also calculated. Qualitative or categorical variables were described as frequencies and proportions. The two study groups (interrupted vs. continuous sedation) were statistically compared using an independent t test or a Mann- Whitney U test (for quantitative variables) and a chi-square test (for categorical variables). Relative risks with their 95% CIs were estimated for various categorical outcomes in the two groups. For time to event data, survival analyses using Kaplan-Meier curves and log rank tests were carried out, followed by Cox regression analyses to adjust for various confounding factors. All tests were two-tailed and a p value of.05 was taken as significant. (n 56) RESULTS One hundred two patients were randomized into two groups, 56 children in the continuous sedation group (group 1) and 46 in the interrupted sedation group (group 2). Both the groups were matched with respect to age, sex, primary diagnosis, severity of illness score (Pediatric Risk of Mortality I and III scores), indication for MV, and initial ventilatory variables (except that the patients in the interrupted sedation group had a lower requirement of PIP and positive endexpiratory pressure at the time of inclusion into the study (Table 1). Primary s (n 46) p Age (yrs), % CI Boy:girl ratio 2.5:1 2.0:1.65 Percentage 71.4 vs vs Pediatric Risk of Mortality score, % CI Pediatric Risk of Mortality III score, % CI Neurological vs. non-neurological 71.4: : illnesses (%) Ventilatory parameters Mode of ventilation, synchronized 89.3 vs vs intermittent mandatory ventilation vs. others (%) FIO 2 (%), % CI Peak inspiratory pressure a (mm Hg), 95% CI Positive end-expiratory pressure a (mm Hg), 95% CI Ventilatory rate (breaths/min), % CI Tidal volume (ml/kg), % CI Died, n CI, confidence interval. a p.05 by Student s t test. Length of MV. The (95% CI for the mean) lengths of MV in the continuous and interrupted sedation groups were ( ) and ( ) days, respectively (Table 2). This difference was statistically significant (p.021). The mean length of MV between both the groups on further Kaplan-Meier analysis (Fig. 1) was also sig- 132

3 Table 2. versus intermittent sedation: Primary and secondary outcomes Variable (n 56) (n 46) p Length of mechanical ventilation (days), ( ) ( ).021 a Number of days awake, ( ) ( ).103 Percentage of awake days, ( ) ( ).005 a Duration of pediatric intensive care unit stay (days), ( ) ( ).048 a Total dose of midazolam (mg/kg/day), ( ) ( ).002 a Total cost of midazolam (rupees), ( ) ( ).020 a Adverse events, n (%) 8 (14.3) 6 (13.0).86 b Pneumothorax, n (%) 7 (12.5) 5 (10.9).79 b Spontaneous extubation, n (%) 1 (1.8) 1 (2.2).88 b CI, confidence interval. a p.05 by Student s t test; b p.05 by the chi-square test. Figure 1. Duration of mechanical ventilation. nificant (13.01 days, 95% CI days, for continuous group vs days, 95% CI days, for interrupted group; p.028). Cox proportional hazard regression analysis was also carried out to see whether the statistical difference between the two study groups for the outcome of time to successful extubation was retained in the presence of certain confounding factors such as the type of presenting illness (general vs. specific organ illness), PIP and positive end-expiratory pressure levels, and indications of MV (respiratory vs. nonrespiratory and neurological vs. nonneurological indications). The results showed that there was still a trend for significance with a hazard ratio of 1.63 (95% CI ; p.07) for early occurrence of extubation in the interrupted sedation group as compared to the continuous sedation group. We also found that the relative risk of patients having received continuous sedation was higher in patients mechanically ventilated for 14 days in comparison to those who received ventilation for 7 and 7 14 days, respectively (relative risk 3.38, 95% CI , p.02; relative risk 2.73, 95% CI , p.04). Length of PICU Stay. The (95% CI for the mean) lengths of MV in the continuous and interrupted sedation groups were ( ) and ( ) days, respectively (Table 2). This difference was found to be statistically significant (p.048). On further Kaplan-Meier analysis (Fig. 2), the median length of PICU stay between both the groups was also significant (14.0 days, 95% CI days, for the continuous group vs days, 95% CI days, for the interrupted group; p.023 by the log rank test). Cox proportional hazard regression analysis was carried out to study the independent predictive ability of intervention for the outcome of time to discharge after adjustment for various confounding factors (same as mentioned above for the length of MV). This showed that there was a statistically significant difference with a hazard ratio of 1.76 (95% CI ; p.02) for early occurrence of discharge in the interrupted sedation group as compared to the continuous sedation group. Secondary s Awake Days on Sedation. The percentage of days a patient was awake in the continuous group was significantly lower as compared to that in the interrupted sedation group (61%, 95% CI 50.8% to 71.32%, vs. 78.8%, 95% CI 73.0% to 84.5%; p.005) (Table 2). On further analysis by taking 3 awake days as a bad outcome and 3 awake days as a good outcome, it was seen that 75% of subjects on continuous sedation as compared to 45.6% of subjects on interrupted sedation had the adverse outcome, giving an absolute risk reduction of 29.4% (95% CI ). The number needed to treat was 4, which meant that about one additional patient for every four patients treated would benefit from interrupted sedation as compared to continuous se- 133

4 lam (mg/kg/day) needed in the interrupted sedation group was significantly reduced as compared to that in the continuous sedation group ( , 95% CI , vs , 95% CI ; p.002) (Table 2). This led to a significant reduction in the average calculated mean cost of midazolam therapy in the interrupted sedation group as compared to the continuous sedation group ( rupees, 95% CI 3,210 6,444 rupees, vs. 13,865 25,338 rupees, 95% CI ,715 rupees; p.020). Adverse Events. The numbers of patients who developed adverse events in both the groups were similar (Table 2). Twelve patients developed pneumothorax, seven in the continuous sedation group and five in the interrupted sedation group (p.79). Children who developed pneumothorax in our study group had high risk disease states such as pneumonia (seven), pulmonary hemosiderosis (two), dengue shock syndrome with acute respiratory distress syndrome (one), acute demyelinating encephalomyelitis (one), and snake envenomation with acute respiratory distress syndrome (one). A total of two episodes of spontaneous extubation were recorded, one each in both the groups. No episodes of accidental removal of peripheral or central catheters were noted in either group. DISCUSSION Figure 2. Duration of pediatric intensive care unit (PICU) stay. LOS, length of stay. Table 3. versus intermittent sedation: Primary outcome Sedation (control) (experimental) Good (Awake 3 Days) Bad (Awake 3 Days) Calculated results: A total of 75.00% of control subjects had the adverse outcome. A total of 45.65% of experimental subjects had the adverse outcome. The difference, the absolute risk reduction, is 29.35%. The 95% confidence interval for this difference ranges from 11.26% to 47.44%. The number needed to treat is 4. This means that about one additional patient for every four patients treated will benefit from the experimental treatment as compared to the control treatment. The 95% confidence interval for the number needed to treat ranges from 2.1 to 8.9. Table 4. versus intermittent sedation: Primary outcome Sedation (control) (experimental) Good ( 50% Awake) Bad outcome ( 50% Awake) Calculated results: A total of 70.91% of control subjects had the adverse outcome. A total of 10.87% of experimental subjects had the adverse outcome. The difference, the absolute risk reduction, is 60.04%. The 95% confidence interval for this difference ranges from 45.04% to 75.04%. The number needed to treat is 2. This means that about one additional patient for every two patients treated will benefit from the intermittent treatment as compared to continuous sedation. The 95% confidence interval for the number needed to treat ranges from 1.3 to 2.2. dation (95% CI for number needed to treat of ). Similarly by taking 50% and 50% awake days as bad and good outcomes, respectively, it was seen that 70.9% of subjects on continuous sedation as compared to 10.9% of subjects on interrupted sedation had the adverse outcome, giving an absolute risk reduction of 60.04% (95% CI 45% 75%). The number needed to treat was 2, which meant that about one additional patient for every two patients treated would benefit from interrupted as compared to continuous sedation (95% CI for number needed to treat of ) (Tables 3 and 4). Total Dose and Cost of Midazolam Therapy. The mean total dose of midazo- Although sedation forms an integral part of ventilatory management in children, the complications of cumulative sedation are concerning. One such concern is its propensity to prolong ventilation (1, 7, 9), thereby increasing the risk of associated complications, such as ventilatorassociated pneumonia (10, 11), upper gastro-intestinal hemorrhage, bacteremia, and venous thromboembolism (7). The lengths of MV and ICU stay thus become important determinants of outcome in ventilated patients. We found that the length of MV and duration of PICU stay were significantly reduced in the interrupted as compared to the continuous sedation protocol. The trend for early occurrence of extubation in the former was retained even in the presence of confounders such as the type of illness, severity of lung involvement (PIP and positive end-expiratory pressure), and indication for MV. Therefore, the statistically significant difference in the baseline PIP and positive end-expiratory pressure levels that was seen between both the groups was possibly not clinically meaningful. Furthermore, the risk of patients having received continuous sedation was approximately 2 3 times higher in patients mechanically ventilated for 14 days in comparison to those who received ventilation for 7 and 7 14 days. Our findings are in concordance with few other studies done in adult patients in which significant reductions in the lengths of ventilation and ICU stay were observed. Kress et al (6) in their study demonstrated a decrease in the median length of ICU stay of 3.5 days in the interrupted sedation group, while Brook et al (1) found that protocol-based sedation was better as it had shown reduction 134

5 in the length of ICU stay from to days (p.01). In patients undergoing coronary artery bypass grafting, Cheng et al (12) demonstrated a reduced ICU stay in patients with the modified sedation protocol as compared to the conventional sedation protocol. However, most of the studies quoted above are adult studies, and there are no studies in children comparing the interrupted sedation protocol with the continuous sedation protocol. We found that the percentage of days awake on sedative infusions was significantly more in the interrupted as compared to the continuous sedation protocol. Our findings are similar to those of Kress et al (6), who showed that the percentage of days during which the patients were awake while receiving a sedative infusion was greater in the interrupted sedation group as compared to the continuous sedation group (85.5% vs. 9.0%; p.001). They also found that various diagnostic tests to rule out new neurological injury are required unnecessarily as the patients on continuous sedation are difficult to assess neurologically (6). Stopping the sedative infusion for a stipulated time during the day in the interrupted sedation protocol helps the clinician to assess patients neurologically. We found that the total dose of midazolam required and the cost of therapy were significantly less in the interrupted as compared to the continuous sedation group, similar to the findings reported by Kress et al 6. ICU care imposes a lot of financial burden on the family, as the major brunt of cost of therapy is borne by parents. Reduced cost of therapy along with reduced hospital stay in the interrupted sedation protocol without an increase in adverse events or other complications is therefore a major advantage in an ICU setting of a developing country such as ours. The frequencies of adverse events in both the groups were similar. The overall frequency for accidental extubation seen in our study was 1.9%, well below the reported rate of 3% to 13% for both neonates and children (13). Kress et al (6) in his adult study reported spontaneous extubations in three (4%) and four (7%) of the patients with interrupted and continuous sedation, respectively (p.88). However, the overall frequency of pneumothorax in our study was 17.1%, higher than the rates of 14% and 11.9% reported previously (14, 15). Barotrauma, volutrauma, and high-risk disease states such as acute respiratory distress syndrome, pneumonia, obstructive airway disease, and aspiration are the major risk factors described for pneumothorax (15). In our study too, the higher frequency of pneumothorax can be explained by the underlying high-risk disease states such as pneumonia, pulmonary hemosiderosis, dengue shock syndrome, acute demyelinating encephalomyelitis, and acute respiratory distress syndrome. The frequencies of pneumothoraces in both groups were however similar. Out of the 12 episodes of pneumothoraces seen in our patients, only four episodes occurred during the interrupted sedation phase. These findings compare favorably with those of Schweickert et al (7), who had shown frequencies of 6.0% and 5% in the continuous and interrupted sedation groups, respectively. CONCLUSIONS To conclude, the length of MV, duration of ICU stay, percentage and number of days awake on sedation, total dose of midazolam, and average calculated cost of the therapy were significantly reduced in the interrupted as compared to the continuous group of sedation. The frequencies of adverse events were similar in both the groups. Reduced cost of therapy in the interrupted sedation protocol, without an increase in adverse events or other complications, becomes a useful factor in a developing country set up like ours where financial constraints are a major impediment to ICU care. REFERENCES 1. 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