Supplementary appendix This appendix formed part of the original submission and has been peer reviewed. We post it as supplied by the authors. Supplement to: Page VJ, Casarin A, Ely EW, et al. Evaluation of early administration of simvastatin in the prevention and treatment of delirium in critically ill patients undergoing mechanical ventilation (MoDUS): a randomised, double-blind, placebo-controlled trial. Lancet Respir Med 2017; published online July 19. http://dx.doi. org/10.1016/s2213-2600(17)30234-5.
Appendix Table 1. Number of patients delirium-free, coma-free by study day. Table 2. Delirium-free, coma-free days at 14 days in patients not CAM-ICU positive (ie CAM- ICU negative or unable to assess due to coma) at randomisation. Table 3. Delirium-free, coma-free days at 14 days in patients who had sepsis and/or ARDS on admission Figure 1: Means plot of C-reactive protein (CRP) mg/l over time Watford ICU ventilator weaning protocol Watford ICU sedation delirium guidelines Additional details for "Figure 1: Trial design" in the Article 1
Table 1: Number of patients delirium-free, coma-free by study day. Number of patients delirium-free and coma-free (Proportion alive, delirium-free and coma-free%) Difference p-value Day Simvastatin (n=71) Placebo (n=71) 1 0 (0 0%) 4 (5 6%) -5 6% 0 04 2 12 (16 9%) 12 (16 9%) 0.0% 1.00 3 14 (19 7%) 14 (23 9%) -4 2% 0 54 4 19 (33 8%) 17 (33 8%) 0 0% 1 00 5 15 (38 0%) 17 (38 0%) 0 0% 1 00 6 11 (36 6%) 21 (46 5%) -9 9% 0 23 7 14 (45 1%) 19 (43 7%) 1 4% 0 87 8 12 (47 9%) 12 (46 5%) 1 4% 0 87 9 11 (47 9%) 11 (47 9%) 0 0% 1 00 10 10 (54 9%) 14 (56 3%) -1 4% 0 87 11 4 (50 7%) 12 (57 7%) -7 0% 0 40 12 6 (54 9%) 10 (57 7%) -2 8% 0 74 13 8 (60 6%) 10 (62 0%) -1 4% 0 86 14 5 (59 2%) 9 (63 4%) -4 2% 0 61 p-value from 2 sample proportions test significance level = 0.05/14 = 0.0036 (Bonferroni Correction) 2
Table 2: Delirium-free, coma-free days at 14 days in patients not CAM-ICU positive (ie CAM- ICU negative or unable to assess due to coma) at randomisation. Delirium/Coma free to 14 days Simvastatin Placebo Difference p-value n=15* n=15* (95% CI) 7 1 (5 2) 7 4 (5 6) -0.3(-4 3, 2 0) 0 89 Mean ±SD presented for treatment arms and Difference (95%CI) from t-test *Simvastatin patients all UTA, placebo patients 4 CAM-ICU negative, 11 UTA. Table 3: Delirium-free, coma-free days at 14 days in patients who had sepsis and/or ARDS on admission Delirium/Coma free to 14 days Simvastatin Placebo Difference p-value n=23 n=18 (95% CI) 5.6±5 2 8.1±5.6-2.6 (-0.8-6.0) 0 13 Mean ±SD presented for treatment arms and Difference (95%CI) from t-test 3
Figure 3: Means plot of C-reactive protein (CRP) mg/l over time 4
Watford General Hospital Ventilator weaning protocol 1 Weaning Weaning should begin as soon as possible. With a primary respiratory pathology such as pneumonia, it may be some time before lung function improves, whereas a post op elective case can be weaned rapidly. Oxygen and PEEP levels should be adjusted to achieve target saturations. Once spontaneous breathing efforts have started, the BILEVEL rate should be reduced and then the ventilator mode changed to SPONT. Pressure support should be adjusted to achieve a target tidal volume. 2 Spontaneous Breathing Trial If the patient is RASS 0 or -1 and CAM negative, is on 30% O2 and 5cm PEEP, then a Spontaneous Breathing Trial can be done. This is either done by disconnecting the ventilator and using a T-piece, or using Tube Compensation (TC) mode on the ventilator. In either case the trial should last no more than 1 hour. If at the end, the patient is comfortable with adequate gases and is not tachypnoeic, then extubate. Do not leave a patient on a T-piece for extended periods. The lack of PEEP may cause atelectasis. Patients only ventilated overnight may well not need a full hour. 3 Weaning intubated patient who failed SBT PEEP equal to or less than 10 Start the day following failed SBT. Set pressure support to achieve a respiratory rate of less than 30. Decrease pressure support by 2 every 2-6 hours. Maximum 6 in any one 24 hours. Decrease until pressure support is 6. Once PS 6 consider extubation dependent on mental status or put patient on tube compensation for up to 2 hours. Do not leave on tube compensation for more than 2 hours. If not extubating maintain patient on PS 6. Remember to do BNP. 4 Weaning tracheostomy patient Set pressure support to achieve a respiratory rate of less than 30. Decrease pressure support by 2 every 2-6 hours. Maximum 6 in any one 24 hours. Decrease until pressure support is 6. Once PS 6 put patient on tracheostomy mask. Leave on TM as long as tolerated up to 12 hours, rest of time on pressure support or assist control. (do not put on and off TM, leave on TM as tolerated). Once patient tolerates 12 hours, leave on TM for as long as tolerated up to 24 hours. Repeat daily until manages 24 hours. Remember to do BNP. Summary Slow: Step-wise relatively slow reduction in pressure support then Fast: Once down to low support use tracheostomy mask continous as tolerated up to 12 hours. 5
Watford ICU Sedation and Delirium Guidelines Regular Review, Reassurance and Reoriententation Objective: Ensure patients on mechanical ventilation are comfortable while avoiding oversedation, enabling communication with the patient and being able to assess the patient for delirium. Goal: Calm, comfortable, responsive patient minimal agitation on minimal sedation. Method: Daily target agreed and confirmed on ward round, highlight on daily record chart. Appropriate as required analgesic, anxiolytic and antipsychotic medication to be prescribed. (Daily goal 0 to -1 unless deeper level clinically indicated.) Background Critically ill patients generally have fragile brains due to inflammation, which is made worse by additional insults such as a sedative drug. Using sedation according to individual patient needs with a protocol driven approach results in a significant reduction in the duration of ventilator days, ICU and hospital stay,the need for tracheostomy and CAT scans. Maintaining optimum level of sedation and the intelligent use of daily interruption of sedatives will protect your patient s brain. Conversely deep sedation in first 48 hours of ventilation is associated with delayed extubation and increase in mortality. Sedated patients have similar EEG readings to sleep deprived patients. How awake is your patient and can they make sense/interact with the environment? Acute cognitive dysfunction, delirium, can be detected by screening. Delirium needs to be specifically tested for, the most common motoric subtype in intensive care is hypoactive it is very easily missed. Brain monitoring tools Sedation Score: Richmond Agitation-Sedation Scale (RASS) Delirium Assessment: Confusion Assessment Method-ICU (CAM-ICU) See Appendix 1. Additional first 24 hours and neurocritical patients: Glasgow Coma Scale Management of intubated and ventilated patients Set sedation goal In all intubated and ventilated patients a sedation goal will be RASS 0 to 1 from outset unless a patient s clinical condition requires a deeper level of sedation e.g. patient with severe ARDS. If the daily sedation goal is not RASS 0 to 1 it must be reviewed and documented on the daily ward round. Assessement Day shift: 3 hourly RASS assessment Night shift: on sedative infusions assess 3 hourly. Do not wake patient up to assess RASS or CAM-ICU if day-time RASS 0. CAM-ICU Assess CAM-ICU twice a shift with at least 4 hours between assessments. If mental status changes repeat CAM-ICU and document nature of change e.g.appears hallucinating. 6
Only record a patient as UTA (unable to assess) if RASS -3 or deeper or severe cerebral pathology e.g. hypoxic brain damage. Standard sedation regime Primary: Fentanyl baseline infusion Secondary: Propofol baseline infusion Add prn bolus administration of 20mgs (2mls) propofol +/- 50mcgm (0.5mls) fentanyl to be given before nursing intervention e.g.turning. Special circumstances A. Patient requiring 48 hours or overnight ventilation: Remifentanil infusions with propofol infusion. See Remifentanil appendix 2. B. Potential organ donor patients or where brainstem tests will be required. C. Patient requiring long-term sedation consider enteral morphine (not if in renal failure) D. Patients requiring propofol infusion >10mls/hr in addition to fentanyl infusion determine cause of agitation and treat accordingly. Anxiety: intermittent 1mg midazolam bolus, maximum 10 mg in 24 hours, Delirium/pain/known anxious patient: Clonidine infusion Delirium: haloperidol bolus prn plus regular iv haloperidol or quetiapine enterally for 48h hours quetiapine enterally Difficulty ventilation/over 200mgs propofol/hr requirement: Paralysis Asthmatics: ketamine plus/minus paralysis. Points regarding Maintenance If a patient is deeply sedated turn the sedation off until the required level of sedation is reached then restart sedation at two-thirds the previous rate. If RASS consisently -2 and deeper daily sedation holds are needed. Immediate management of agitation 2ml bolus of sedative infusion, then follow delirium management. After the first 12 hours some patients will only require opioid infusions. Patients with hypoactive delirium may be easily ventilated on an opioid infusion alone. Morphine, midazolam and fentanyl will accumulate in all patients. Remember Propofol infusion syndrome Delirium CAM-ICU A patient cannot be assessed as negative for delirium without using a validated assessment. 7
Delirious patients are able to nod to questions e.g. are you comfortable? And obey direct commands e.g. stick out your tongue. You will miss delirium unless you test for it. The CAM-ICU is used on all patients whether on sedation or not. Patients RASS -3 and deeper are Unable To be Assessed UTA. Patients RASS -2 and above are either CAM-ICU positive or CAM-ICU negative. If they do not engage in squeezing your hand at all they are too delirious to do so. An obviously confused patient can be documented as CAM-ICU without formal assessment. Less delirious patients can pass CAM-ICU but inattention can be determined by asking them to count months of years backwards (7 months correctly is a pass). Delirium Establish cause and treat cause there may be more than one. Patients with agitated delirium require 1 to 1 nursing, preferably in a side room. The environment, noise and events in a main bed area will exacerbate the patients distress Haloperidol should only be used to manage episodes of agitation (RASS +2 and above) Before using haloperidol: 12 lead ECG and note QTc, measure electrolytes and correct potassium and magnesium if required. Use haloperidol with caution in patients with a QTc greater than 450 msecs. Do not use haloperidol at all if QTc greater than 500 msecs. Repeat ECG 12 to 24 hours after using haloperidol. Discontinue haloperidol if QTc increases more than 25% from baseline or to over 500 msecs. Give haloperidol 2.5mg to 5 mgs intravenously according to patient age and weight. Wait 30 minutes, if patient is still agitated double dose and repeat. Wait 30 minutes, if patient is still agitated olanzapine 5mgs to 10mgs intramuscularly. If at any time immediate control needed for patient or staff safety use 1mg boluses of midazolam intravenously repeated as necessary. Otherwise avoid the use of benzodiazepines except in patients with alcohol withdrawal. Ongoing agitation: if interfering with care e.g. repeated pulling out of NG tube consider 25mgs enteral quetiapine 12 hourly, increase as necessary up to 100mgs 12 hourly. Family: Patients families witnessing delirium find it distressing. They will need to know more about delirium and reassured. There is an information sheet available in the relatives waiting area. (Appendix 3) The use of restraints needs to be documented in medical notes, reason communicated to relatives and reviewed daily. Only use soft wrist bands secured to sides of beds with some movement of arms allowed or Posey mitts. See Trust restraint and mental capacity act policies. Note Propofol infusions in non-intubated patients The use of low dose propofol infusions should be avoided in non-intubated patients. If they are considered necessary to control agitation for patient safety and allow medical and nursing treatment the patient will need constant supervision and one to one nursing. Propofol can quickly cause respiratory obstruction and apnoea. It should be used for the minumum time necessary and usually to enable relief of agitation to be established with an anti-psychotic and/or clondine. A patient on propofol infusion should be RASS 0 or -1 i.e awake or easily aroused by voice. Selected References 8
Barr J et al. Clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit. Crit Care Med. 2013; 41(1):263-306. Skrobik Y et al Protocolized intensive care unit management of analgesia, sedation, and delirium improves analgesia and subsyndromal delirium rates. Anesth Analg. 2010 Aug; 111:451-463. Mehta S et al SLEAP Investigators; Canadian Critical Care Trials Group. Daily sedation interruption in mechanically ventilated patients cared for with a sedation protocol. A randomised controlled trial. JAMA. 2012 Nov 21;308:1985-1992 Schweickert WD et al. Early physical and occupational therapy in mechanically ventilated, critically ill patients: a randomised controlled trial. The Lancet 2009, 373(9678):1874-82. Epub 2009 May 14. National Institute of Health and Clinical Excellence (NICE) July 2010: http://publications.nice.org.uk/delirium-cg1. Page VJ et al. Effect of intravenous haloperidol on the duration of delirium and coma in critically ill patients (Hope-ICU): a randomised, double-blind, placebo-controlled trial. Lancet Respir Med 2013; 1: 515-523 Gusmao-Flores D et al. The Confusion Assessment Method for the Intensive Care Unit (CAM- ICU) and Intensive Care Delirium Screening Checklist (ICDSC) for the diagnosis of delirium: a systematic review and meta-analysis of clinical studies. Crit Care. 2012; 16(4):R115. Ely EW et al Delirium as a predictor of mortality in mechanically ventilated patients in the Intensive Care Unit. JAMA 2004;291:1753-62 Pandharipande PP et al. Long-term cognitive impairment after critical illness. N Engl J Med 2013, 369:1306-16. Bruera E et al. The impact of delirium and recall on the level of distress in patients with advanced cancer and their family care givers. Cancer 2009; 115(9): 2004-2012 Appendix 1 Richmond Agitation-Sedation Scale RASS +4 Combative Overtly combative, violent, immediate danger to staff +3 Very agitated Pulls or removes tube(s) or catheter(s), aggressive +2 Agitated Frequent nonpurposeful movement, fights ventilator +1 Restless Anxious but movements not aggressive or vigorous 0 Alert and calm -1 Drowsy Not fully alert, but has sustained awakening (eye-opening/eye contact) to voice (>10 secs) -2 Light sedation Briefly awakes with eye contact to voice (<10 seconds) -3 Moderate Movement or eye opening to voice (but no eye contact) sedation -4 Deep sedation No response to voice, but movement or eye opening to physical stimulation -5 Unarousable No response to voice or physical stimulation Physical stimulation = shaking shoulder and /or rubbing sternum 9
Confusion assessment method-icu to detect delirium CAM-ICU Feature 1: Acute onset of mental status changes or fluctuating course AND Feature 2: Inattention SAVEAHAART 2 mistakes on hand squeeze on A AND / OR Feature 3: Disorganised thinking 4 questions, one command 1 error allowed Feature 4: Altered level of consciousness 10
Additional details for "Figure 1: Trial design" in the Article Listed according to first reason for exclusion. Please note one patient* had 3 reasons listed. Accounts for the 51 extra reasons to make a total of 1073 exclusion criteria as listed. 1 was pregnant or breastfeeding and was expected to be discharged within 48h of admission 1 had creatine kinase concentration>10 times the upper limit of normal range and had known allergy to statin drugs 3 had creatine kinase concentration>10 times the upper limit of normal range and had alanine transaminase concentrations>8 times the upper limit of normal range 1 had creatine kinase concentration>10 times the upper limit of normal range and had severe renal impairment 3 had creatine kinase concentration>10 times the upper limit of normal range and had current or recent treatment (within 2 weeks) with statins 2 had creatine kinase concentration>10 times the upper limit of normal range and were likely to withdraw from treatment within 48h 1 had alanine transaminase concentrations>8 times the upper limit of normal range and had severe liver disease 3 had alanine transaminase concentrations>8 times the upper limit of normal range and were likely to withdraw from treatment within 48 hours. 1 had alanine transaminase concentrations>8 times the upper limit of normal range and did not speak English or did not adequately understand verbal or written nformation 1 was receiving ongoing and sustained treatment with any of the following: itraconazole, ketoconazole, HIV protease inhibitors, nefazodone, cyclosporine, amiodarone, verapamil, diltiazem, gemfibrozil, or danazol and had severe renal impairment 2 were receiving ongoing and sustained treatment with any of the following: itraconazole, ketoconazole, HIV protease inhibitors, nefazodone, cyclosporine, amiodarone, verapamil, diltiazem, gemfibrozil, or danazol and had current or recent treatment (within 2 weeks) with statins. 1 had uncomplicated elective surgery and had known allergy to statin drugs 1 had uncomplicated elective surgery and had creatine kinase concentration>10 times the upper limit of normal range 2 had uncomplicated elective surgery and had current or recent treatment (within 2 weeks) with statins. 1 expected to be discharged within 48h of admission and known allergy to statin drugs 1 had severe liver disease and were likely to withdraw from treatment within 48h 1 had current or recent treatment (within 2 weeks) with statins and had creatine kinase concentration>10 times the upper limit of normal range 2 had current or recent treatment (within 2 weeks) with statins and had alanine transaminase concentrations>8 times the upper limit of normal range *1 had current or recent treatment (within 2 weeks) with statins AND had alanine transaminase concentrations>8 times the upper limit of normal range AND had severe renal impairment 5 had current or recent treatment (within 2 weeks) with statins and were receiving ongoing and sustained treatment with any of the following: itraconazole, ketoconazole, HIV protease inhibitors, nefazodone, cyclosporine, amiodarone, verapamil, diltiazem, gemfibrozil, or danazol 5 had current or recent treatment (within 2 weeks) with statins and had uncomplicated elective surgery 1 had current or recent treatment (within 2 weeks) with statins and was expected to be discharged within 48 hours 1 had current or recent treatment (within 2 weeks) with statins and had contraindication to enteral drug administration 2 had current or recent treatment (within 2 weeks) with statins and were likely to withdraw from treatment within 48h 1 did not consent and were likely to withdraw from treatment with 48h 1 were likely to withdraw from treatment with 48h and had alanine transaminase concentrations>8 times the upper limit of normal range 4 were likely to withdraw from treatment with 48h and had current or recent treatment (within 2 weeks) with statins 1 patient had two reasons listed as Other