Terapeutisk hypotermi - analgesi og sedasjon

Sedasjon ved terapeutisk hypotermi 2012 Hva og hvorfor Kjernetemperatur 32 - 34°C Bedrer overlevelse og nevrologisk funksjon etter iskemisk/anoksiske insult 32 – 34, innen 6 timer etter insult Organpreservasjon/proteksjon, hjerne og hjerte traumatic brain (og medulla spinalis) injury, stroke, neonatal hypoxic-ischemic encephalopathy, hemorrhagic shock, hjerteinfarkt Fra når for CA og newborns Sedasjon ved terapeutisk hypotermi 2012

Sedasjon ved terapeutisk hypotermi 2012 Hvordan Intern (iskalde infusjoner, kateterbasert) Ekstern (kjølehjelm, ispakninger, kjøleteppe, kjøledress) Oppstart snarest, mål: terapitp. innen 6 timer etter skade Varighet 12 - 72 timer Oppvarming 0.5°C/1 - 2 time(r) til 36°C Kalde infusjoner, kjøledress, kjølehette etc - gjerne bilde 12 – 72 timer Internal cooling methods using infusion of cold fluids Internal cooling methods using catheter-based technologies Surface cooling helmet Surface cooling with blankets or surface heat-exchange device and ice Surface cooling with ice packs Sedasjon ved terapeutisk hypotermi 2012

Sedasjon ved terapeutisk hypotermi 2012 Hvilke barn? Etter hjertestans Ved asfyksi hos nyfødte Ved traumatisk hjerneskade Sedasjon ved terapeutisk hypotermi 2012

Sedasjon ved terapeutisk hypotermi 2012 Behov for sedasjon? ✔ Ja, som hovedregel, nedfelt bl.a. i skandinaviske retningslinjer - kontroll med muskelskjelvinger - lindre ubehag og smerte Ja, som hovedregel Hvorfor? Kuldeskjelvinger (- brunt fett), ubehag/smerte Sedasjon ved terapeutisk hypotermi 2012

Spesielle utfordringer Iskemisk skade på flere organsystemer enn hjerne/CNS - redusert nyre- og/eller leverfunksjon Hypotermien i seg selv - Endret medikamentomsetning - Endret medikamenteffekt Endret kinetikk/dynamikk Iskemisk skade på flere organsystemer Hypotermien Sedasjon ved terapeutisk hypotermi 2012

Hva vet vi? - hypotermien i seg selv Midazolam - Opptil 5 ganger økt midazolamkonsentrasjon hos hypotermi behandlede vs normoterme pasienter Propofol - 0pptil 30% økt plasmakonsentrasjon v/hypotermi Fentanyl - Opptil 3.7 ganger reduksjon i clearance Remifentanil - ? Div. studier som fokuserer på metabolisme Redusert metabolisme og eliminasjon Endret medikamentrespons Medikamentvalg, pauser Remifentanil or fentanyl is used for pain control and intermittent lorazepam is recommended for sedation. Our goal is to provide comfort but to also allow for frequent neurological assessment. Neuromuscular blockade with vecuronium or cisatracurium are often continued during maintenance hypothermia if there is difficulty sustaining target temperature, and drug ‘‘holidays’’ are employed daily. Cisatracurium is preferred when there is evidence of hepatic or renal injury. Some patients have significant lung injury and may require neuromuscular blockade for ade- quate oxygenation and ventilation. We are mindful that many of the drugs we give to our patients can have their kinetics and function dramatically affected by body tem- perature [34]. Current practice guidelines recommend analgesic, sedative, and NMBD administration during therapeutic hypothermia procedures renal or hepatic dysfunction secondary to prolonged cardiac arrest, so metabolism and elimination of these drugs are delayed for an unpredictable amount of time. In addition, the myocar- dial dysfunction after cardiac arrest makes patients more susceptible to hemodynamic complications. Finally, in- duced hypothermia itself produces delays in metabolism and clearance of most drugs, modifying drug response, particularly potency and efficacy.19,20,63 Therefore, inad- equate use of sedation and NMBDs prolongs recovery and also delays the time to reliable evaluation of neurologic status and prognosis. Midazolam metabolism may be altered in patients with hepatic dys- function, and in renal dysfunction, their active metabolites could accumulate. In addition, Fukuoka et al.64 reported a 5-fold increase in midazolam plasma concentrations in traumatic brain-injured patients treated with hypothermia (32°C–34°C) compared with normothermic patients Propofol, its potential toxicity may be in- creased in hypothermia. In this situation, the plasmatic concentration could increase up to 30% compared with the concentration achieved in normothermic patients receiving the same dose; reduced intercompartmental clearance be- tween the central and peripheral compartments can prob- ably justify this finding.63 Use of high-dose infusions has been associated with the propofol infusion syndrome, which includes significant cardiovascular toxicity. Fentanyl, Metabolism and clearance of fentanyl are modified during hypothermia; there are studies showing a decrease up to 3.7 times in the fentanyl clearance in this situation,68 so the high dose could produce significant delays in the awakening time after fentanyl infusion interruption. Morphine, its effect is unpredictable during hy- pothermia treatment; the effect of morphine could be increased because of active metabolite accumulation if renal dysfunction is present or it could be reduced because of a decrease in morphine 􏰋 receptor affinity in a hypothermic situation.19 Most recommendations include using NMBDs to quickly achieve the hypothermia target and to avoid shiv- ering during hypothermia treatment. Shivering produces undesirable responses, such as increased oxygen consump- tion, excessively laborious breathing, faster heart rate, and a general stress-like response. NMBDs are very effective in prevent- ing and controlling shivering and are devoid of major adverse hemodynamic effects, giving them great advan- tages in hemodynamically unstable patients.16 However, their metabolism could also be affected in hypothermic situations and in patients with organic dysfunctions, espe- cially during steroid NMBD use. Active metabolites of vecuronium and pancuronium accumulate in patients with renal dysfunction, producing undesired prolonged residual paralysis. Rocuronium metabolism is decreased if there is hepatic dysfunction. Thirty-three of the ICUs included in this study used pancuronium or vecuronium, and 10 se- lected rocuronium. Monitoring of paralysis depth with TOF is recom- mended to prevent steroid NMBD accumulation, but this monitoring loses its utility during hypothermia. Peripheral nerve conduction is slowed by cooling and is not a reliable monitoring method at temperatures in this treatment. Paralytic drugs may mask seizure activity. However, controlling epileptic seizures has not yet been demonstrated to improve neurologic progno- sis. It is also important to emphasize that paralysis may mask insufficient sedation, Clinicians must carefully select drugs with the lowest possible toxicity in this specific situation to avoid delays in consciousness recovery time and therefore mistakes in the initial prognosis after hypothermia discon- tinuation, prolongation in mechanical ventilation time, complications derived from the latter, as well as the con- tribution to hemodynamic instability. It is necessary to detect seizures in paralyzed patients and to obtain data that could help with patient prognosis without interference produced by the chosen drug. We use remifentanil with or without propofol as the sedoanal- gesia regimen and cisatracurium, 0.1 mg/kg/h, as an NMBD to prevent shivering. Sedoanalgesia titration is guided by using the BIS Monitor (Aspect Medical Systems, Natick, MA). If the initial admission BIS value is 􏰁40, we initiate remifentanil at a dose of 6 􏰋g/kg/h. If the BIS value is 􏰂40, we add propofol to maintain BIS values between 40 and 60. Because the requirements of propofol in mild hypothermia are decreased to achieve the same effect, the BIS monitor enables us to administer the exact dose of propofol to reach the targeted BIS value and to avoid deleterious effects. We do not use TOF monitoring with a peripheral nerve stimulator to measure the depth of paraly- sis during therapeutic hypothermia, but we use it after rewarming. When rewarming is started, at a temperature of 36°C, cisatracurium perfusion is discontinued. When a TOF ratio is 􏰂0.9, propofol infusion is discontinued and we initiate a gradual reduction in the remifentanil dosage until recovery of consciousness. We think that with this protocol, we reach the goals of sedoanalgesia and neuromuscular blockade in patients submitted to therapeutic hypothermia after cardiac arrest because (1) it ensures adequate analge- sia and sedation; (2) the abnormal epileptiform EEG waves can be identified on the BIS monitor and the different numerical data can help to detect nonconvulsive seizures72; (3) we avoid accumulation of drugs that could distort later neurologic examination; and (4) the protocol permits fast recovery of consciousness and neurologic examination after the sedation infusion is halted. Despite the fact that the three previ- ously mentioned neuromuscular block- ing agents are eliminated by different pathways, each agent showed an increase in duration of action by mild hypother- mia caused by reduced ClS. In light of the significant increase in the duration of ac- tion, clinicians using neuromuscular blocking agents in hypothermic patients should reduce doses and monitor neuro- muscular function to avoid overdose, which occurs with mild increases in the duration of action of these agents. Sedasjon ved terapeutisk hypotermi 2012

Hva vet vi? - hypotermien i seg selv Morfin - Helt uforutsigbar efffekt  opphopning av aktiv metabolitt  redusert reseptoraffinitet Nevromuskulære blokkere - Forlenget effekt pga redusert clearance Div. studier som fokuserer på metabolisme Redusert metabolisme og eliminasjon Endret medikamentrespons Medikamentvalg, pauser Remifentanil or fentanyl is used for pain control and intermittent lorazepam is recommended for sedation. Our goal is to provide comfort but to also allow for frequent neurological assessment. Neuromuscular blockade with vecuronium or cisatracurium are often continued during maintenance hypothermia if there is difficulty sustaining target temperature, and drug ‘‘holidays’’ are employed daily. Cisatracurium is preferred when there is evidence of hepatic or renal injury. Some patients have significant lung injury and may require neuromuscular blockade for ade- quate oxygenation and ventilation. We are mindful that many of the drugs we give to our patients can have their kinetics and function dramatically affected by body tem- perature [34]. Current practice guidelines recommend analgesic, sedative, and NMBD administration during therapeutic hypothermia procedures renal or hepatic dysfunction secondary to prolonged cardiac arrest, so metabolism and elimination of these drugs are delayed for an unpredictable amount of time. In addition, the myocar- dial dysfunction after cardiac arrest makes patients more susceptible to hemodynamic complications. Finally, in- duced hypothermia itself produces delays in metabolism and clearance of most drugs, modifying drug response, particularly potency and efficacy.19,20,63 Therefore, inad- equate use of sedation and NMBDs prolongs recovery and also delays the time to reliable evaluation of neurologic status and prognosis. Midazolam metabolism may be altered in patients with hepatic dys- function, and in renal dysfunction, their active metabolites could accumulate. In addition, Fukuoka et al.64 reported a 5-fold increase in midazolam plasma concentrations in traumatic brain-injured patients treated with hypothermia (32°C–34°C) compared with normothermic patients Propofol, its potential toxicity may be in- creased in hypothermia. In this situation, the plasmatic concentration could increase up to 30% compared with the concentration achieved in normothermic patients receiving the same dose; reduced intercompartmental clearance be- tween the central and peripheral compartments can prob- ably justify this finding.63 Use of high-dose infusions has been associated with the propofol infusion syndrome, which includes significant cardiovascular toxicity. Fentanyl, Metabolism and clearance of fentanyl are modified during hypothermia; there are studies showing a decrease up to 3.7 times in the fentanyl clearance in this situation,68 so the high dose could produce significant delays in the awakening time after fentanyl infusion interruption. Morphine, its effect is unpredictable during hy- pothermia treatment; the effect of morphine could be increased because of active metabolite accumulation if renal dysfunction is present or it could be reduced because of a decrease in morphine 􏰋 receptor affinity in a hypothermic situation.19 Most recommendations include using NMBDs to quickly achieve the hypothermia target and to avoid shiv- ering during hypothermia treatment. Shivering produces undesirable responses, such as increased oxygen consump- tion, excessively laborious breathing, faster heart rate, and a general stress-like response. NMBDs are very effective in prevent- ing and controlling shivering and are devoid of major adverse hemodynamic effects, giving them great advan- tages in hemodynamically unstable patients.16 However, their metabolism could also be affected in hypothermic situations and in patients with organic dysfunctions, espe- cially during steroid NMBD use. Active metabolites of vecuronium and pancuronium accumulate in patients with renal dysfunction, producing undesired prolonged residual paralysis. Rocuronium metabolism is decreased if there is hepatic dysfunction. Thirty-three of the ICUs included in this study used pancuronium or vecuronium, and 10 se- lected rocuronium. Monitoring of paralysis depth with TOF is recom- mended to prevent steroid NMBD accumulation, but this monitoring loses its utility during hypothermia. Peripheral nerve conduction is slowed by cooling and is not a reliable monitoring method at temperatures in this treatment. Paralytic drugs may mask seizure activity. However, controlling epileptic seizures has not yet been demonstrated to improve neurologic progno- sis. It is also important to emphasize that paralysis may mask insufficient sedation, Clinicians must carefully select drugs with the lowest possible toxicity in this specific situation to avoid delays in consciousness recovery time and therefore mistakes in the initial prognosis after hypothermia discon- tinuation, prolongation in mechanical ventilation time, complications derived from the latter, as well as the con- tribution to hemodynamic instability. It is necessary to detect seizures in paralyzed patients and to obtain data that could help with patient prognosis without interference produced by the chosen drug. We use remifentanil with or without propofol as the sedoanal- gesia regimen and cisatracurium, 0.1 mg/kg/h, as an NMBD to prevent shivering. Sedoanalgesia titration is guided by using the BIS Monitor (Aspect Medical Systems, Natick, MA). If the initial admission BIS value is 􏰁40, we initiate remifentanil at a dose of 6 􏰋g/kg/h. If the BIS value is 􏰂40, we add propofol to maintain BIS values between 40 and 60. Because the requirements of propofol in mild hypothermia are decreased to achieve the same effect, the BIS monitor enables us to administer the exact dose of propofol to reach the targeted BIS value and to avoid deleterious effects. We do not use TOF monitoring with a peripheral nerve stimulator to measure the depth of paraly- sis during therapeutic hypothermia, but we use it after rewarming. When rewarming is started, at a temperature of 36°C, cisatracurium perfusion is discontinued. When a TOF ratio is 􏰂0.9, propofol infusion is discontinued and we initiate a gradual reduction in the remifentanil dosage until recovery of consciousness. We think that with this protocol, we reach the goals of sedoanalgesia and neuromuscular blockade in patients submitted to therapeutic hypothermia after cardiac arrest because (1) it ensures adequate analge- sia and sedation; (2) the abnormal epileptiform EEG waves can be identified on the BIS monitor and the different numerical data can help to detect nonconvulsive seizures72; (3) we avoid accumulation of drugs that could distort later neurologic examination; and (4) the protocol permits fast recovery of consciousness and neurologic examination after the sedation infusion is halted. Despite the fact that the three previ- ously mentioned neuromuscular block- ing agents are eliminated by different pathways, each agent showed an increase in duration of action by mild hypother- mia caused by reduced ClS. In light of the significant increase in the duration of ac- tion, clinicians using neuromuscular blocking agents in hypothermic patients should reduce doses and monitor neuro- muscular function to avoid overdose, which occurs with mild increases in the duration of action of these agents. Sedasjon ved terapeutisk hypotermi 2012

Sedasjon ved terapeutisk hypotermi 2012 Hvordan sedere? Medikamentvalg - Remifentanil eller fentanyl for analgesi - Propofol eller midazolam for sedasjon - Cisatracurium Medikamentpauser hvert døgn Effektmonitorering - Overvåke grad ev nevromuskulær blokkade; TOF - Overvåke sdasjongrad; BIS, EEG - Konsentrasjonsmålinger EEG, BIS TOF, kanskje ikke pålitelig fordi perifer nerveledning er langsommere ved hypotermi Medikamentvalg, pauser Remifentanil or fentanyl is used for pain control and intermittent lorazepam is recommended for sedation. Our goal is to provide comfort but to also allow for frequent neurological assessment. Neuromuscular blockade with vecuronium or cisatracurium are often continued during maintenance hypothermia if there is difficulty sustaining target temperature, and drug ‘‘holidays’’ are employed daily. Cisatracurium is preferred when there is evidence of hepatic or renal injury. Some patients have significant lung injury and may require neuromuscular blockade for ade- quate oxygenation and ventilation. We are mindful that many of the drugs we give to our patients can have their kinetics and function dramatically affected by body tem- perature [34]. Current practice guidelines recommend analgesic, sedative, and NMBD administration during therapeutic hypothermia procedures renal or hepatic dysfunction secondary to prolonged cardiac arrest, so metabolism and elimination of these drugs are delayed for an unpredictable amount of time. In addition, the myocar- dial dysfunction after cardiac arrest makes patients more susceptible to hemodynamic complications. Finally, in- duced hypothermia itself produces delays in metabolism and clearance of most drugs, modifying drug response, particularly potency and efficacy.19,20,63 Therefore, inad- equate use of sedation and NMBDs prolongs recovery and also delays the time to reliable evaluation of neurologic status and prognosis. Midazolam metabolism may be altered in patients with hepatic dys- function, and in renal dysfunction, their active metabolites could accumulate. In addition, Fukuoka et al.64 reported a 5-fold increase in midazolam plasma concentrations in traumatic brain-injured patients treated with hypothermia (32°C–34°C) compared with normothermic patients Propofol, its potential toxicity may be in- creased in hypothermia. In this situation, the plasmatic concentration could increase up to 30% compared with the concentration achieved in normothermic patients receiving the same dose; reduced intercompartmental clearance be- tween the central and peripheral compartments can prob- ably justify this finding.63 Use of high-dose infusions has been associated with the propofol infusion syndrome, which includes significant cardiovascular toxicity. Fentanyl, Metabolism and clearance of fentanyl are modified during hypothermia; there are studies showing a decrease up to 3.7 times in the fentanyl clearance in this situation,68 so the high dose could produce significant delays in the awakening time after fentanyl infusion interruption. Morphine, its effect is unpredictable during hy- pothermia treatment; the effect of morphine could be increased because of active metabolite accumulation if renal dysfunction is present or it could be reduced because of a decrease in morphine 􏰋 receptor affinity in a hypothermic situation.19 Most recommendations include using NMBDs to quickly achieve the hypothermia target and to avoid shiv- ering during hypothermia treatment. Shivering produces undesirable responses, such as increased oxygen consump- tion, excessively laborious breathing, faster heart rate, and a general stress-like response. NMBDs are very effective in prevent- ing and controlling shivering and are devoid of major adverse hemodynamic effects, giving them great advan- tages in hemodynamically unstable patients.16 However, their metabolism could also be affected in hypothermic situations and in patients with organic dysfunctions, espe- cially during steroid NMBD use. Active metabolites of vecuronium and pancuronium accumulate in patients with renal dysfunction, producing undesired prolonged residual paralysis. Rocuronium metabolism is decreased if there is hepatic dysfunction. Thirty-three of the ICUs included in this study used pancuronium or vecuronium, and 10 se- lected rocuronium. Monitoring of paralysis depth with TOF is recom- mended to prevent steroid NMBD accumulation, but this monitoring loses its utility during hypothermia. Peripheral nerve conduction is slowed by cooling and is not a reliable monitoring method at temperatures in this treatment. Paralytic drugs may mask seizure activity. However, controlling epileptic seizures has not yet been demonstrated to improve neurologic progno- sis. It is also important to emphasize that paralysis may mask insufficient sedation, Clinicians must carefully select drugs with the lowest possible toxicity in this specific situation to avoid delays in consciousness recovery time and therefore mistakes in the initial prognosis after hypothermia discon- tinuation, prolongation in mechanical ventilation time, complications derived from the latter, as well as the con- tribution to hemodynamic instability. It is necessary to detect seizures in paralyzed patients and to obtain data that could help with patient prognosis without interference produced by the chosen drug. We use remifentanil with or without propofol as the sedoanal- gesia regimen and cisatracurium, 0.1 mg/kg/h, as an NMBD to prevent shivering. Sedoanalgesia titration is guided by using the BIS Monitor (Aspect Medical Systems, Natick, MA). If the initial admission BIS value is 􏰁40, we initiate remifentanil at a dose of 6 􏰋g/kg/h. If the BIS value is 􏰂40, we add propofol to maintain BIS values between 40 and 60. Because the requirements of propofol in mild hypothermia are decreased to achieve the same effect, the BIS monitor enables us to administer the exact dose of propofol to reach the targeted BIS value and to avoid deleterious effects. We do not use TOF monitoring with a peripheral nerve stimulator to measure the depth of paraly- sis during therapeutic hypothermia, but we use it after rewarming. When rewarming is started, at a temperature of 36°C, cisatracurium perfusion is discontinued. When a TOF ratio is 􏰂0.9, propofol infusion is discontinued and we initiate a gradual reduction in the remifentanil dosage until recovery of consciousness. We think that with this protocol, we reach the goals of sedoanalgesia and neuromuscular blockade in patients submitted to therapeutic hypothermia after cardiac arrest because (1) it ensures adequate analge- sia and sedation; (2) the abnormal epileptiform EEG waves can be identified on the BIS monitor and the different numerical data can help to detect nonconvulsive seizures72; (3) we avoid accumulation of drugs that could distort later neurologic examination; and (4) the protocol permits fast recovery of consciousness and neurologic examination after the sedation infusion is halted. Despite the fact that the three previ- ously mentioned neuromuscular block- ing agents are eliminated by different pathways, each agent showed an increase in duration of action by mild hypother- mia caused by reduced ClS. In light of the significant increase in the duration of ac- tion, clinicians using neuromuscular blocking agents in hypothermic patients should reduce doses and monitor neuro- muscular function to avoid overdose, which occurs with mild increases in the duration of action of these agents. Sedasjon ved terapeutisk hypotermi 2012

Sedasjon ved terapeutisk hypotermi 2012 Uemper ved sedasjon Hemodynamiske effekter Maskerer krampeanfall/status Vanskeliggjør prognostisering Hemodynamikk Prognostisering Krampedeteksjon Propofol infusjonssyndrom: melkesyre acidose, cardiovask. instab., bradyarytmi Sedasjon ved terapeutisk hypotermi 2012

Anesth Analg 2010;110:1328-1334 Sedasjon ved terapeutisk hypotermi 2012