INTRODUCTION

Sedation and analgesia are essential for the majority of patients who require mechanical ventilation in the intensive care unit (ICU).^(1-5) Sedation reduces the stress response, provides anxiolysis, and improves tolerance for ventilatory support. However, sedative drugs have been associated with adverse effects, which result in prolonged ventilatory support and lengthy hospital stays.^(3,6,7)

Different studies have shown that the use of protocols, sedation scoring systems, and daily interruption of sedative agents may reduce the duration of mechanical ventilation and the length of the ICU stay.^(8-11) However, there is reportedly a wide variation of sedation schemes and practices used in ICUs worldwide, and 32-57% of the patients are deeply sedated or are sedated at deeper levels than required.^(1,2,4,5) Analgesia has been suggested to be the first step toward improving comfort in mechanically ventilated patients.^(12,13) Recent data have suggested that an analgesia-based sedation protocol reduces the use of hypnotics and may improve the practice of sedation in patients who require mechanical ventilation.^(14-16)

In the present study, we evaluate the clinical practice of analgesia and sedation in critically ill patients who require mechanical ventilation for more than 48 hours. Based on these findings, we designed and implemented an analgesia based, goal-directed, nurse-driven sedation protocol and evaluated its impact on the duration of mechanical ventilation, the deepness of sedation and the prevalence of post-traumatic stress disorder symptoms one year after mechanical ventilation.

METHODS

Intervention group

In August 2006, a one-day workshop was performed with the participation of at least one nurse and one physician from every ICU to define the prospective sedation protocol. The data from the observational period were presented and discussed. A key finding was the high proportion of patients in deep sedation.⁽¹⁷⁾ Based on this finding, an analgesia-based, goal-directed, nurse-driven sedation protocol was designed for the research team. This proposal was discussed in group sessions, and it was finally approved by all of the participants.

This protocol can be summarized in the following steps. The attending physician defined a daily goal of sedation, usually SAS 3-4. A deep level of sedation (SAS 1-2) was allowed in the presence of severe respiratory failure (PaO₂/FiO₂ ratio <150 with PEEP ≥10cm H₂O, significant patient-ventilator asynchrony, non-conventional modes of mechanical ventilation, or high-minute ventilation) or severe-cardiovascular failure (high doses of vasoactive drugs, cardiac index <2.0L/min/m² or arterial lactate >4mmol/L). Fentanyl (from 0.6µg/kg/h to 3.6µg/kg/h) and midazolam (from 0.015mg/kg/h to 0.09mg/kg/h) by continuous i.v. infusions were titrated according to a prescribed table, generating 12 different levels of drugs (Table 1). To avoid deep sedation and to manage pain control, fentanyl was applied in the first three levels before starting midazolam.⁽¹²⁾ This table was designed based on the observed doses of fentanyl and midazolam during the observational phase.⁽¹⁷⁾ At any time, i.v. boluses were allowed before increasing the infusion rates of the sedatives. If the patient was agitated despite the administration of maximal doses (fentanyl 3.6µg/kg/h and midazolam 0.09mg/kg/h), an increase in midazolam doses or a third drug was allowed according to the directions of the staff physician. Haloperidol was recommended for agitation and delirium. In the present trial, we did not implement a systematic evaluation for the diagnosis of delirium. Neuromuscular blockade (NMB) was not routinely used. However, it was allowed in patients with severe respiratory failure and asynchrony, and its requirement was assessed daily. Deep sedation was assured before starting NMB.

Table 1 - Continuous infusion rates for both fentanyl and midazolam, which started at level 3 (fentanyl 1.8μg/kg/min and no midazolam)

Infusion level	1	2	3	4	5	6	7	8	9	10	11	12
Fentanyl (μg/kg/h)	0.6	1.2	1.8	1.8	2.4	2.4	3	3	3.6	3.6	3.6	3.6
Midazolam (mg/kg/h)	0	0	0	0.015	0.015	0.03	0.03	0.045	0.045	0.06	0.075	0.09

Table 1 - Continuous infusion rates for both fentanyl and midazolam, which started at level 3 (fentanyl 1.8μg/kg/min and no midazolam)

The nurse/bed ratio in Chile is typically 1:3-4. Once the patient was intubated, fentanyl was started at 1.8µg/kg/h (level 3), and drug infusions were titrated to ensure that the patient remained calm and cooperative or mildly sedated (SAS 3 or 4). If the daily goal was SAS 1 or 2, drug infusions were increased. At least 4 daily SAS evaluations were recommended.

Once the protocol was designed, an educational program with onsite training was provided for all of the nurses and physicians working in each ICU. During these sessions, the data from the observational phase were disclosed, as well as the newly designed protocol. Daily sedation goals and SAS evaluations were reinforced. Recruitment of patients for the intervention period started in late October 2006 and ended in January 2007.

RESULTS

During the observational and interventional periods, we reviewed 634 and 598 patients who required mechanical ventilation, respectively. After we reviewed the exclusion criteria, we enrolled 155 (24.4%) patients in the observational group and 132 (22.1%) patients in the interventional group (e-supplement). Both groups were comparable in admission diagnosis, severity of illness and co-morbidities (Table 2).

Table 2 - Baseline demographics of patients

APACHE II - Acute Physiology and Chronic Health Evaluation II; SOFA - Sequential Organ Failure Assessment; ALI/ARDS - acute lung injury and acute respiratory distress syndrome; COPD - chronic obstructive pulmonary disease; PEEP - positive end-expiratory pressure. The results are expressed as the number (percentages), the median (interquartile range) or the mean±standard deviation.

Extended data relative to the observational group have been previously published.⁽¹⁷⁾ Midazolam and fentanyl were the most frequently used drugs for sedation and analgesia during mechanical ventilation. They were used in 133 (85.8%) patients and 126 (81.3%) patients, respectively. Propofol, morphine and lorazepam were used in only 17 (10.9%) patients, 26 (16.8%) patients and 6 (3.9%) patients, respectively.

During the interventional phase, the application of the protocol increased the dose of fentanyl and decreased that of midazolam (Table 3). Twenty-five percent of the patients in the interventional group did not require midazolam infusions. Neuromuscular blocker use was not significantly reduced in the interventional group (Table 3).

Table 3 - Midazolam and fentanyl doses from days 1 to 7 and use of haloperidol and muscle relaxants

There were 1,640 SAS evaluations in the observational group and 1,350 SAS evaluations in the interventional group. The proportion of SAS scores 3-4 increased from 37.1% to 48.7% in the interventional group, whereas SAS scores 1-2 decreased from 55.2% to 44.0% (p=0.001) (Figure 1). Agitation did not change between the periods and remained at approximately 7%.

Figure 1 - Percentage of sedation-agitation score evaluations in level 1-2 (deep sedation and coma), level 3-4 (mild sedation or awake) and level 5-7 (agitation) in both groups during the first week (p=0.001). SAS - Sedation-Agitation Score.

Download

Figure 1 - Percentage of sedation-agitation score evaluations in level 1-2 (deep sedation and coma), level 3-4 (mild sedation or awake) and level 5-7 (agitation) in both groups during the first week (p=0.001). SAS - Sedation-Agitation Score.

The time on mechanical ventilation, the number of ventilator-free days, the length of the ICU and hospital stay and 28-day mortality were similar in both groups (Table 4). Safety issues related to the interventional protocol did not differ from the observational period (Table 4). Two patients in the interventional group were retired from the protocol because of adverse effects, which were likely related to high doses of fentanyl (both patients had ileus and intra-abdominal hypertension).

Table 4 - Major and safety outcomes in the observational and intervention groups

The one-year mortality for the entire population was 49% (142/287), and 52% of the survivors (75/149) answered the PTSS-10 questionnaire (42 could not be reached, 14 refused consent, and 14 were unable to respond). The average PTSS-10 score was 29±14, and 20 (27%) patients had scores >35, without differences between the groups (Table 5). No relationship was found between hypnotics, analgesics and NMB use and doses, or the level of sedation during mechanical ventilation and PTSD symptoms. Patients with traumatic memories had a greater prevalence of PTSS-10 >35 (p<0.005).

Table 5 - Traumatic memories and post-traumatic stress syndrome-10 (PTSS-10) scale at one year

DISCUSSION

In the present two-phase, multicenter, single nation-wide study, the design and application of an analgesia-based, goal-directed, nurse-driven sedation protocol did not show significant differences in major outcomes. However, the present protocol was shown to be safe and feasible in our population and demonstrated decreased time in deep sedation. Additionally, post-traumatic stress disorder symptoms in survivors one year after mechanical ventilation were comparable between the groups.

Analgesia-based sedation, which has been used primarily in the surgical field⁽²¹⁾ and more recently in the general mixed population,^(15,16,22) is a relatively new term in the ICU. Analgesia is not usually measured and is sometimes ignored during mechanical ventilation.⁽¹⁴⁾ Although sedation guidelines recommend that sedation be started only after providing adequate analgesia,^(12,13) a significant proportion of the patients in recent trials did not receive opioids or pain management as needed.^(23,24) Moreover, in a large Italian sample of postoperative patients who underwent elective or emergency surgery, 49% did not receive any opioids.⁽²⁵⁾ When we designed the protocol during the workshop, we wanted to ensure adequate analgesia before administering hypnotics.

During the observational phase, we found that a large proportion (approximately 50%) of the patients were in deep states of sedation, similar to the study of Payen et al.⁽²⁾ Midazolam and, in a lesser proportion, propofol were mostly used in our patients. When we applied our protocol, we strongly reduced the use of midazolam and observed a 10% reduction in the number of patients in deep sedation, which was a persistent finding during the first week of mechanical ventilation. However, we could not determine if the positive impact on the level of sedation observed in the interventional group could have been achieved because of the systematic use of a sedation scale, because of the decrease in the midazolam requirement, or both.⁽¹¹⁾

Hypnotics are associated with recognized side effects, such as deeper levels of sedation, hemodynamic depression, longer times on mechanical ventilation, and more recently, delirium and chronic cognitive dysfunction.^(7,14,16,26) Opioids have long been recognized as hypnotic-sparing drugs, which could lighten the level of sedation, facilitate patient evaluation, hasten awakening and decrease the time on mechanical ventilation.^(15,16) The hypnotic-sparing effect we obtained with our protocol compares closely to the findings in the study of Park et al., who found that 37% of patients in a mixed medical-surgical population did not require hypnotics during ventilatory support when an analgesia-based sedation regimen was instituted.⁽¹⁵⁾

One controversial finding of the present study was that the application of an analgesia-based sedation protocol decreased the incidence of deep sedation but failed to decrease the duration of mechanical ventilation. The study was designed to detect a 20% difference in ventilator-free days, which seems to be a very obtainable effect, based on the literature.^(8-10) The use of continuous infusions, which may prolong the duration of mechanical ventilation, may explain this lack of benefit.⁽²⁶⁾ However, cultural barriers are hard to challenge because of the low nurse/bed ratio in our country. By introducing a nurse-driven, goal-directed protocol, we may have established a first step in a patient-safety initiative for sedating patients who require mechanical ventilation in our country.

The use of drugs with relatively long elimination half-times, such as midazolam and fentanyl, could also explain this lack of benefit. For instance, Carson et al. showed that patients required less time on mechanical ventilation when propofol was used, instead of lorazepam, despite nearly tripling the dose of morphine in the propofol group.⁽²⁷⁾

Several other reasons can explain this negative trial, such as the lack of a protocol for weaning from mechanical ventilation, which may have a major impact on the time required for mechanical ventilation.⁽²⁴⁾ This fact also reflects the heterogeneity in the care in the involved ICU (e-supplement). Moreover, the intensity of activities in our protocol was low, compared to recent trials.⁽¹³⁾ More frequent evaluations of the sedation level and interventions may have shown a major clinical impact. However, we observed that the present protocol was safe and feasible.

Finally, by decreasing the depth of sedation, we expected a lower incidence of PTSD symptoms.^(28-31) However, no differences were found between drug exposure or level of sedation and the development of PTSD. The high rate of missed data, mostly from patients from rural zones, may preclude us from generating additional conclusions in this regard.

CONCLUSIONS

We designed and implemented an analgesia-based, goal-directed, nurse-driven sedation protocol in a multicenter, single nation-wide study. Despite the fact that there was no improvement in major outcomes, we observed that the present protocol was demonstrated to be safe and feasible and that it showed decreased periods in deep sedation without increased agitation. This may be a first step in a patient-safety initiative for sedating mechanically ventilated patients in Chile.