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Summary

  1. Top of page
  2. Summary
  3. Methods
  4. History
  5. Cases recorded
  6. Mechanism of PRIS
  7. Pathophysiological features of PRIS
  8. Preventing PRIS in the critically ill
  9. Early markers of PRIS
  10. Management
  11. References

The clinical features of propofol infusion syndrome (PRIS) are acute refractory bradycardia leading to asystole, in the presence of one or more of the following: metabolic acidosis (base deficit > 10 mmol.l−1), rhabdomyolysis, hyperlipidaemia, and enlarged or fatty liver. There is an association between PRIS and propofol infusions at doses higher than 4 mg.kg−1.h−1 for greater than 48 h duration. Sixty-one patients with PRIS have been recorded in the literature, with deaths in 20 paediatric and 18 adult patients. Seven of these patients (four paediatric and three adult patients) developed PRIS during anaesthesia. It is proposed that the syndrome may be caused by either a direct mitochondrial respiratory chain inhibition or impaired mitochondrial fatty acid metabolism mediated by propofol. An early sign of cardiac instability associated with the syndrome is the development of right bundle branch block with convex-curved (‘coved type’) ST elevation in the right praecordial leads (V1 to V3) of the electrocardiogram. Predisposing factors include young age, severe critical illness of central nervous system or respiratory origin, exogenous catecholamine or glucocorticoid administration, inadequate carbohydrate intake and subclinical mitochondrial disease. Treatment options are limited. Haemodialysis or haemoperfusion with cardiorespiratory support has been the most successful treatment.

Propofol is commonly used in anaesthesia and in intensive care where its favourable pharmacokinetics and rapidly reversible sedation make it an ideal drug for short-term sedation. However, propofol has been associated with a number of serious adverse effects such as metabolic acidosis, cardiac asystole, myocardial failure, rhabdomyolysis, and death [1–33]. Although previous reports have described severe metabolic acidosis during propofol infusion in children, cases have been described in adult patients more recently [3, 4, 6–8, 10, 13–23]. In 1998, Bray proposed the term ‘propofol infusion syndrome’ (PRIS) to describe this clinical state associated with propofol infusions in children [5]. The clinical features of PRIS that were originally described in children include acute refractory bradycardia leading to asystole in the presence of one or more of the following: metabolic acidosis (base deficit > 10 mmol.l−1), rhabdomyolysis, hyperlipidaemia and an enlarged or fatty liver. There is a strong association between PRIS and propofol infusions at doses greater than 4 mg.kg−1.h−1 of longer than 48 h duration [5]. The mechanisms by which this syndrome occurs have not been elucidated but there is in vitro evidence that suggests impaired mitochondrial function [27]. The management of patients with this syndrome involves cardiovascular support with cardiac pacing and haemofiltration [27–33].

The aim of this article is to review the clinical features, pathophysiology and management of propofol infusion syndrome (PRIS).

Methods

  1. Top of page
  2. Summary
  3. Methods
  4. History
  5. Cases recorded
  6. Mechanism of PRIS
  7. Pathophysiological features of PRIS
  8. Preventing PRIS in the critically ill
  9. Early markers of PRIS
  10. Management
  11. References

An electronic search was performed using the Ovid interface for Medline (1963–2006), CINAHL and EMBASE database. The following terms were searched separately and then combined to identify relevant articles: propofol, arrhythmias, metabolic acidosis, lipidaemia, head injuries, and rhabdomyolysis. The titles and abstracts of the generated references were examined for relevance. The bibliographies of the articles were also scanned for additional references, i.e. ‘reference dredging’.

History

  1. Top of page
  2. Summary
  3. Methods
  4. History
  5. Cases recorded
  6. Mechanism of PRIS
  7. Pathophysiological features of PRIS
  8. Preventing PRIS in the critically ill
  9. Early markers of PRIS
  10. Management
  11. References

The first case of PRIS-related death was in Denmark in 1990, and the Danish Side-effects Committee issued a warning about the use of propofol infusions in children [1]. The patient was a 2-year-old girl with croup who was sedated for 4 days with a propofol infusion (10 mg.kg−1.h−1) and developed metabolic acidosis, heart failure, hypotension and hepatomegaly. However, this case report did not receive much attention because the syndrome had not been identified at the time. In 1992, it was a report by Parke et al. [2] that caused real concern. The authors reported five deaths in children aged 4 weeks to 6 years who were admitted to the paediatric intensive care unit for the management of severe respiratory tract infections. The children, who were ventilated and sedated with propofol infusion (7–10 mg.kg−1.h−1 for between 66 and 115 h), developed metabolic acidosis, hyperlipidaemia, hepatomegaly, bradyarrhythmias and, ultimately, progressive cardiac failure. This was a hallmark publication and proposed a link between propofol infusions and mortality. Following this, a child (20 months old) with epiglottitis developed PRIS associated with a propofol infusion (mean rate 7.4 mg.kg−1.h−1) over 56 h [28]. Unlike the previous reports, this patient, the first recorded survivor of PRIS, was resuscitated from asystolic cardiac arrest and veno-venous haemofiltration was undertaken to treat the acidosis. Cornfield et al., in a retrospective review of a case series of 142 critically ill children who were sedated with continuous propofol infusion at doses less than 3 mg.kg−1.h−1, found no association between propofol infusion doses and metabolic acidosis or haemodynamic instability. They concluded that propofol could be safely and effectively used to provide sedation in the paediatric intensive care unit [34]. However, the dose range was below the dose (4 mg.kg−1.h−1) associated with propofol toxicity. Statistically, this study was limited by the small sample size [35].

In 2001, an unpublished randomised controlled trial of the use of propofol infusions involving 327 patients in a paediatric intensive care unit in the US recorded an increase in the 28-day mortality in propofol-treated patients with a trend toward statistical significance [36]. The group that did not receive propofol had a mortality of 4%, whereas those who received 1% propofol infusion had an 8% mortality, and those who received 2% propofol infusions had an 11% mortality. The baseline disease severity scores were similar for the three groups. The trial was terminated early and the United States Food and Drug Agency issued a warning against the use of propofol for long-term sedation in the paediatric population.

However, in 1996, a case report described the occurrence of severe metabolic acidosis in a 30-year-old woman with acute respiratory failure (caused by asthma) who was sedated with a propofol infusion [37]. The patient developed a worsening metabolic acidosis (increased anion gap) despite the absence of hypoxia, hypotension, sepsis, shock, diabetes or catecholamine administration. Lactic acidosis resolved 12 h after the propofol infusion was ceased and she was extubated without event. This case suggested that an early metabolic acidosis may signal the onset of PRIS. The first recorded death from PRIS in an adult was in 1998 in a patient with refractory epilepsy who received a propofol infusion (rate 8.8–17.5 mg.kg−1.h−1 over 44 h). Metabolic acidosis, hypotension, hyperkalaemia and rhabdomyolysis preceded a wide complex bradycardia and ultimately asystole despite resuscitation [4]. In 2001, Cremer et al., in a retrospective cohort study from an adult neurosurgical intensive care unit, reported that seven of 67 adult patients with head injury who received propofol infusion for sedation showed signs of PRIS and died [3]. The authors estimated that the odds ratio for the occurrence of PRIS for every mg.kg−1.h−1 increase in mean propofol dose above 5 mg.kg−1.h−1 was 1.93 (CI 1.12–3.32, p = 0.018). When the investigators retrospectively reanalysed the ECGs of these seven patients, they found that six patients had developed right bundle branch block with convex-curved (‘coved type’) ST segment elevation in the right praecordial leads (V1 –V3) similar to that observed in patients with the Brugada syndrome [38] (Fig. 1). Brugada syndrome is an inherited sudden cardiac death syndrome caused by a defect in ion channels in the myocardium which causes electrical instability by augmenting outward currents and/or reducing inward currents at the end of phase 1 in the cardiac action potential. These electrocardiographic changes precede the malignant ventricular arrhythmias that cause sudden cardiac death in these patients.

image

Figure 1.  Right bundle branch block with convex-curved (‘coved’) ST elevation [*] in V1 to V3 usually precedes malignant ventricular arrhythmias in propofol infusion syndrome.

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More reports of unexplained early metabolic acidosis developing in patients who were not critically ill on high dose propofol infusions of short duration emerged [13, 17, 18, 39]. A 31-year-old woman received propofol sedation for a radiofrequency ablation procedure for chronic atrial fibrillation [16]. Metabolic acidosis occurred (pH 7.3, BE − 8 mmol.l−1) after 395 min of propofol infusion and this resolved gradually upon cessation of the infusion. The authors concluded that the metabolic acidosis was caused by propofol alone because no other causes for the metabolic acidosis existed. They suggested that PRIS may be reversible in the early stages, and emphasised that high dose, prolonged infusions of propofol should be avoided.

In 2004, the Australian Adverse Drug Reactions Committee issued a warning concerning the use of propofol for sedation in adult intensive care units and recommended that propofol should not be infused at rates greater than 4 mg.kg−1.h−1[40].

Cases recorded

  1. Top of page
  2. Summary
  3. Methods
  4. History
  5. Cases recorded
  6. Mechanism of PRIS
  7. Pathophysiological features of PRIS
  8. Preventing PRIS in the critically ill
  9. Early markers of PRIS
  10. Management
  11. References

Cases recorded in the literature are summarised in Tables 1–4. Although PRIS was initially considered a syndrome associated with paediatric patients, it is now evident that it can occur in adults. To date, 32 paediatric and 29 adult cases have been recorded in the literature. Of these, 20 paediatric and 18 adult patients died, and 12 paediatric and 11 adult patients survived. Seven of the 12 paediatric patients and one of the 11 adult patients who survived had the hallmarks of PRIS, whereas the other patients had either metabolic acidosis or other early signs of PRIS. Seven of 61 cases reported occurred during general anaesthesia using propofol infusions. Most of the cases reported had either respiratory or central nervous system (CNS) illness (22 with respiratory disease, and 33 with neurological disease).

Table 1.   Deaths in Paediatric PRIS patients.
Case No.Sex (M/F)Age; yearsDiagnosis [Reference]Mean dose; mg.kg−1.h−1 (duration)Clinical featuresTreatment
  1. NA, not applicable; RBBB, right bundle branch block; BE, base excess; VF, ventricular fibrillation; VT, ventricular tachycardia; CK, creatine kinase; SAH, subarachnoid haemorrhage; SDH, sub-dural haematoma; VEB, ventricular ectopic beats.

1F 2.17Laryngotracheobronchitis  (Croup) [1]10.2 (4 days)Cardiac failure,metabolic acidosis,NA
2F 2.75Laryngotracheobronchitis  (Croup) [2]7.5 (115 h)RBBB, bradycardia, asystole Metabolic acidosis, BE − 11.8 Lipidaemia, hepatomegaly, feverAtropine, inotropes
3F 1.33Laryngotracheobronchitis  (Croup) [2]7.4 (66 h) l−1Bradycardia, heart block, asystole Metabolic acidosis, BE − 10.5 Lipidaemia, hepatomegaly, acute  renal failure Bilateral lung consolidationInotropes Propofol ceased Perioneal dialysis Haemofiltration
4F 1.83Laryngotracheobronchitis  (Croup) [2]10 (76 h)Bradycardia, asystole Metabolic acidosis, BE − 9.2,  lipidaemia Fever, lung consolidationInotropes Cardiac pacing
5F 0.08Bronchiolitis [2]8 (64 or 74 h)Bradycardia, atrial ectopics Metaolic acidosis, BE − 22.8,  lipidaemia Hepatomegaly, acute renal failure  respiratory failurePropofol infusion ceased Atropine, Isoprenaline Peritoneal dialysis
6M 6Laryngotracheobronchitis  (Croup) [2]8.1 (104 h)Bradycardia, asystole Metabolic acidosis, BE − 16 Lipidaemia, acute renal failure SepsisInotropes Transvenous pacing Propofol ceased
7NANALaryngitis, epiglottitis  [62]Range 5–9 (>48 h)Metabolic acidosis HepatomegalyNA
8M 9Upper respiratory infection  Influenza A [24]4.5 (72 h)Bradycardia, VT, asystole Cardiac failure, hepatomegaly,  feverAtropine, Inotropes
9NA<2.6Epiglottitis [5]5.2 (4 days)Bradycardia, asystole Metabolic acidosis Hepatomegaly with fatty changeNA
10NA 1.08Laryngitis, encephalitis  [5]6.3 (4 days)Bradycardia, AV block Metabolic acidosis Hepatomegaly with fatty changeNA
11F11Brain tumour resection  PICU sedation post-op  [25]9.4 (38 h)Junctional rhythm, VT, VF Hypotension Metabolic acidosis, BE − 21 Lipidaemia, acute renal failure  hyperkalaemia, feverPropofol infusion ceased Inotropes, bicarbonate Glucose and insulin Lidocaine, bretylium Cardioversion
12NA 3.83NA [5]200 mg.h−1 (2 days)Cardiac arrhythmia, respiratory  failure Metabolic acidosisNA
13NA 1.08Laryngotracheobronchitis  (Croup) [5]NA (2 days)Cardiac failureNA
14NA 0.5Congenital heart disease  [5]? 6 (> 72 h)Bradycardia, hepatomegaly,  respiratory failureNA
15NA 8Status epilepticus [5]15.2 (29 h)Bradycardia, asystole Metabolic acidosis Fever 38.4 °C CK 38770 U.l−1 MyoglobinuriaNA
16M 6Laryngitis [26]? 5–10 (60 h)Nodal bradycardia andl  tachycardia, VT Heart failure, meatbolic acidosis Lipidaemia, fever, CK > 33 000 U.l−1 MyoglobinuriaInotropes Dantrolene
17M 7Focal motor status  epilepticus [4]20 (63 h)Tachycardia, bradycardia, asystole Metabolic acidosis Rhabdomyolysis, CK 49992 U.l−1 Acute renal failure, fever, hypoxiaPropofol infusion ceased  inotropes, phenylephrine Dialysis
18F13Closed head injury [9]6 (96 h)RBBB, circulatory failure SAH, SDH Metabolic acidosis, fever,  pneumonia RhabdomyolysisPropofol infusion ceased Inotropes
19F 3.08Aspiration pneumonia  [12]20 (15 h)  ceased for 13 h,  then 4.2 (8 h)Bradycardia, VEB's, Incomplete RBBB Metabolic acidosis, BE < −10  lipidaemia, fever, hepatomegaly Rhabdomyolysis, CK 2000 U.l−1Inotropes Propofol infusion ceased External pacemaker Transvenous pacemaker
20M10Status epilepticus [11]NA (>48 h)RBBB, polymorphic VT, Torsades  de pointes Cardiac failure, hyperlipidaemia,  fever Metabolic acidosis, hepatomegalyLidocaine, Magnesium, Propofol infusion ceased Esmolol, inotropes
Table 2.   Survivors in paediatric PRIS patients.
Case No.Sex (M/F)Age; yearsDiagnosis [Reference]Mean dose; mg.kg−1.h−1 (duration)Clinical featuresTreatment
  1. Abbreviations – see Table 1. Plus PICU, paediatric intensive care unit; ARF, acute renal failure; ECMO, extra-corporeal membrane oxygenation; AVM, atrerio-venous malformation; GA, general anaesthesia.

1F 1.67Epiglottitis [28]7.4 (56 h)Bradycardia, asystole Metabolic acidosis, BE − 17 Lipidaemia, renal failure, fever Rhabdomyolysis, CK > 100 000 U.l−1Propofol infusion ceased Adrenaline, dobutamine,  Ca++ Bicarbonate infusion Veno–veno haemofiltration
2M 4Laryngitis with sub-glottic  stenosis [33]8.6 (3 days)Lipidaemia, elevated serum carnitine Rhabdomyolysis, CK 127 000 U.l−1 Pulmonary hypertensionPropofol infusion ceased Bicarbonate Veno–veno haemofiltration
3F 0.83Upper respiratory tract  obstruction due to  oesophageal foreign body  [29]10 (50.5 h)RBBB, 1st degree HB, bradycardia Metabolic acidosis, BE − 13 Lipidaemia, fever, hepatomegaly Rhabdomyolysis, CK 31785 U.l−1Propofol infusion ceased Cardiac pacing Plasmapharesis Veno–veno haemofiltration Bicarbonate, inotropes
4NA 1.5Bilateral talipes repair  under GA [41]6 (5 h)Bradyarrhythmias Cardiac failure, acute renal failure Metabolic acidosis, BE − 17Bicarbonate infusion Inotropes Peritoneal dialysis
5M 2Gunshot wound to head  [27]5.2 (72 h)Nodal bradycardia, cardiac failure  acute renal failure Metabolic acidosis, BE − 10 Rhabdomyolysis, myoglobinaemia Lipidaemia, Troponin 0.04 μg.l−1 Elevated total carnitine 66 μmol.l−1 Elevated C5 acylcarnitine 8.4 μmol.l−1 Elevated manonylcarnitine 3.3 μmol.l−1Propofol infusion ceased Isoprenaline Transvenous pacing Haemofiltration
6M13AVM resection PICU sedation post op  [32]NA (4 days)Cardiac failure, Rhabdomyolysis ARFPropofol infusion ceased ECMO Haemodialysis
7M 7Osteogenesis imperfecta ORIF femur under GA Respiratory tract infection  [55]13.5 (2.4 h)Metabolic acidosis, BE − 8.3Propofol infusion ceased
8F 5Embolisation of cerebral AVM, PICU post op [54]Range 6–15 (10 h)Metabolic acidosis, BE − 5.6Propofol infusion ceased
9M 0.42Cleft lip repair PICU sedation post op  [30]11.7 (approx. 72 h)Tachy- and bradyarrhythmias, VT Cardiac failure, metabolic acidosis Lipidaemia, rhabdomyolysis Acute renal failure, liver failure Coagulopathy Elevated free acylcarnitine intermediatesPropofol infusion ceased  inotropes External pacing Charcoal haemoperfusion Dialysis
10M13Parietal AVM resection PICU sedation post op  [31]Range 3–8.4 (> 74 h)Increased QT interval, polymorphic VT Cardiac failure Metabolic acidosis Rhabdomyolysis ARF, myoglobinuria Pulmonary OedemaPropofol infusion ceased Cardioversion Lidocaine, amiodarone Inotropes, bicarbonate ECMO Haemodialysis
11F11Recurrent seizures  [42]4.7 (130 h)Elevated C4 acyl–carnitine 2.1 μmol.l−1Propofol infusion ceased
12M 7Craniosyntosis PICU sedation post op  [50]NA (0.66 h)Metabolic acidosis, BE − 7.8Propofol infusion ceased
Table 3.   Deaths in adult PRIS patients.
Case No. Sex (M/F) Age; yearsDiagnosis [Reference]Mean dose; mg.kg−1.h−1 (duration) Clinical features Treatment
  1. Abbreviations – see previous tables plus LBBB, left bundle branch block; PEA, pulseless electrical activity; SVT, supraventricular tachycardia; VT, ventricular tachycardia; AF, atrial fibrillation; CPK, creatinine phosphokinase.

1M 17Refractory epilepsy [4]11.2 (44 h)Wide complex bradycardia, asystole Hypotension, hypoxia, metabolic  acidosis Rhabdomyolysis, hyperkalaemia, feverPropofol infusion ceased Bicarbonate, calcium Atropine
2NA>18Closed head injury [14]7.6 (55 h)Cardiovascular collapse Metabolic acidosis, acute renal failureNA
3F 47Asthma [8]12 (> 48 h)VT, asystole, metabolic acidosis Myoglobinuria, ARF, hyperkalaemia CK 762 000 U.l−1, troponin I 4 mg.l−1Dopamine, phenylephrine Haemodialysis
4M 18Closed head injury Intracerebral haemorrhage  [10]Range 5.8–7.6 (98 h)LBBB, bradycardia, PEA, asystole Cardiac failure, lipidaemia, fever Metabolic acidosis, BE − 24 Myoglobinuria, hyperkalaemiaAtropine, adrenaline
5NA 16–55Head injury [3]7.3 (> 58 h)VT, rhabdomyolysis, hyperkalaemiaNA
6NA 16–55Head injury [3]5.7 (> 58 h)Sinus tachycardia, SVT Cardiac failure, metabolic acidosis, Rhabdomyolysis, hyperkalaemiaNA
7NA 16–55Head injury [3]6.6 (> 58 h)AF, VT, metabolic acidosis, lipidaemia Metabolic acidosis, hyperkalaemiaNA
8NA 16–55Head injury [3]5.5 (> 58 h)ST, Idioventricular rhythm, cardiac failure Metabolic acidosis, rhabdomyolysisNA
9NA 16–55Head injury [3]7.4 (> 58 h)SVT, VT, cardiac failure, metabolic  acidosis Rhabdomyolysis, hyperkalaemiaNA
10NA 16–55Head injury [3]5.8 (> 58 h)SVT, Nodal rhythm, VT, lipidaemia Metabolic acidosis, hyperkalaemiaNA
11NA 16–55Head injury [3]6.9 (> 58 h)Sinus tachycardia, idioventricular  rhythm Metabolic acidosis, lipidaemia,  hyperkalaemiaNA
12F 21AVM embolisation [6] 4.5–9 (>48 h)Cardiac failure Metabolic acidosis, BE − 19.1,  lactate 15 mmol.l−1Propofol infusion ceased Dopamine
13F 23Status epilepticus [15]12 (106 h)Tachycardia, cardiac failure,  metabolic acidosis Acute renal failure, hyperkalaemiaNA
14M 31Closed head injury and  seizure [7]4.1 (157 h)Polymorphic VT, VF, metabolic  acidosis Hyperlipidaemia, rhabdomyolysis Acute renal failure, CK 11 000 U.l−1NA
15M 42Cerebral sinus thrombosis  [13] 0–8.6 (>120 h)Cardiac failure, metabolic acidosis  acute renal failure, CK 22426 U.l−1Propofol infusion ceased Phenylephrine
16F 27Seizures after AV malformation embolisation [20]dose NA; 36 hMetabolic acidosis, hypotension  bradycardiaInotropes, pacing, fluids
17M 64Status epilepticus [20]dose NA; 24 hMetabolic acidosis, rhabdomyolysis  hypotension, raised CPK, cardiac arrestInotropes, bicarbonate
18F 24Status epilepticus,  encephalitis [20]dose NA; 44 hBradyarrhthymias, hypotension  Metabolic acidosisInotropes, cardiac pacing
Table 4.   Survivors in adult PRIS patients.
Case No. Sex (M/F)Age; years Diagnosis [Reference]Mean dose; mg.kg−1.h−1 (duration) Clinical features Treatment
  1. Abbreviations – see previous tables plus TIVA, total intravenous anaesthesia.

1F30Asthma [37]NA (12.75 h)Metabolic acidosis, lactate 8.6 mmol.l−1Propofol infusion ceased
2M41Asthma [8]NA (ca 144 h)Cardiac failure Rhabdomyolysis, CK 204 000 U.l−1 Myoglobinuria acute renal failure Troponin I 46 μg.l−1NA
3F31Propofol TIVA RFA pulmonary vein  [17]4.98 (6.6 h)Metabolic acidosisPropofol infusion ceased Bicarbonate
4M64Propofol TIVA Laparoscopic radical  prostatectomy [17]7.8 (ca 4.5 h)Tachycardia Metabolic acidosisPropofol infusion ceased
5F17Closed head injury Intra-abdominal  haemorrhage [13]> 4 (> 48 h)Metabolic acidosis RhabdomyolysisPropofol infusion ceased Haemodialysis
6M42Brainstem resection of  caverous angioma  [18]Range 2.3–9  (21 h and 7.5 h)Metabolic acidosis ARF Rhabdomyolysis MyoglobinuriaPropofol infusion ceased
7M40C-spine stabilisation  (TIVA propofol) Post op sedation in ICU  [19]3 (72 h)Metabolic acidosis Rhabdomyolysis ARF Fever 41 oCDantrolene Propofol infusion ceased Veno–veno haemofiltration
8F18Status Asthmaticus  [37]NA (3 h)Metabolic acidosis, BE − 10,  lactate 12 mmol.l−1Propofol infusion ceased
9M45Cardiac surgery  [21]2.6 (8 h)Metabolic acidosis, VT, cardiac failurePropofol ceased, inotropes  Amiodarone
10M30Quadriplegia, sepsis  [22]5.5 ( 56 h)Atrial fibrillation, lactic acidosis,  raised CPK Cardiac ischaemiaPropofol ceased
11M21Head injury [23]6.8 (42 h)Tachycardia, cardiac dysfunction,  metabolic acidosis BE 13.4; renal  failureAcidosis improved when  propofol ceased

Mechanism of PRIS

  1. Top of page
  2. Summary
  3. Methods
  4. History
  5. Cases recorded
  6. Mechanism of PRIS
  7. Pathophysiological features of PRIS
  8. Preventing PRIS in the critically ill
  9. Early markers of PRIS
  10. Management
  11. References

Early theories about the cause of acidosis in PRIS included impaired hepatic lactate metabolism caused by intralipid present in propofol leading to lactate accumulation and acidosis, accumulation of inactive propofol metabolites, and lipid microembolisation [2, 5, 37]. However, recent research has focused on impaired mitochondrial respiratory chain function. Whether the mitochondrial defect caused by propofol is mediated by an unidentified metabolite [29, 41] or by an underlying neuromuscular defect is widely debated. Cray et al. supported the theory that a propofol metabolite caused a biochemical lesion that disrupted the respiratory chain (as evidenced by a reduction in mitochondrial muscle cytochrome C oxidase), causing a failure of ATP production, cellular hypoxia and metabolic acidosis [29]. Mehta et al. demonstrated a reduced complex IV activity and cytochrome oxidase ratio in the mitochondria in in-vitro studies [41]. Studies utilising guinea pig heart tissue confirmed that propofol either impairs oxygen utilisation or inhibits electron flow along the mitochondrial electron transport chain in cardiomyocytes [42] (Fig. 2).

image

Figure 2.  Inhibitory actions of propofol at the mitochondrial electron transport chain. Inhibition of coenzyme Q at Complex II and cytochrome c at Complex IV causes a failure of ATP production. Co Q = coenzyme Q; Cyt C = cytochrome c.

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Wolf et al. reported raised serum levels of malonylcarnitine, C5-acylcarnitine, creatine kinase, troponin T, triglyceride, lactate and myoglobinaemia in a 2-year-old child with PRIS. They postulated that propofol caused a disruption of mitochondrial fatty-acid oxidation [27] (Fig. 3). Long-term propofol infusion was associated with an increase in malonylcarnitine, which inhibits carnitine palmityl transferase, a mitochondrial transport protein. Consequently, the entry of long chain acylcarnitine esters in muscle tissue is impaired. Medium chain and short chain fatty acids diffuse into the mitochondria and inhibit the respiratory chain (at complex II), resulting in a rise in C5, C4 or C2-acylcarnitine [27, 30, 43]. This causes a failure of ATP production in the mitochondria, leading to a build up of long chain, medium chain and short chain fatty-acid metabolic by-products. Soya bean (added to propofol to enhance its solubility) increases the medium and long chain triglyceride fat load. As a consequence of impaired fatty-acid oxidation, a rapid build up of toxic fatty-acid intermediates results and when this is coupled with cellular hypoxia, it worsens the acidosis [30, 43]. Excess serum fatty-acid concentrations cause ventricular arrhythmias [31, 44]. A case report speculated that PRIS was precipitated by the commencement of a ketogenic diet (high fat, low carbohydrate) as adjuvant therapy for refractory status epilepticus in a 10-year-old boy sedated with propofol [11]. It suggested that the fat load, coupled with propofol-mediated impairment of mitochondrial fatty-acid oxidation, caused the metabolic acidosis.

image

Figure 3.  Effects of propofol on fatty acid metabolism at the mitochondria. Sites where propofol inhibits the conversion of free fatty acids to acyl-coA causing a failure of fatty acid oxidation and ATP production.

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PRIS mimics the mitochondrial myopathies in which there are specific defects in the mitochondrial respiratory chain associated with mitochondrial DNA abnormalities [45]. The clinical features of a mitochondrial myopathy result from a disturbance in lipid metabolism in cardiac and skeletal muscle. The patients are well until stressed by infection or starvation, when they metabolise fat to produce energy. Under these conditions, they develop severe rhabdomyolysis, cardiac and hepatic insufficiency associated with hypoglycaemia [45, 46]. Steiner et al. [47] and Farag et al. [48] recommended that propofol should not be used in patients with an inborn error of mitochondrial fatty-acid metabolism (very long chain acyl-coenzyme A dehydrogenase deficiency) because it interfered with fatty-acid oxidation and caused severe metabolic acidosis.

Pathophysiological features of PRIS

  1. Top of page
  2. Summary
  3. Methods
  4. History
  5. Cases recorded
  6. Mechanism of PRIS
  7. Pathophysiological features of PRIS
  8. Preventing PRIS in the critically ill
  9. Early markers of PRIS
  10. Management
  11. References

One common feature of PRIS is myocardial failure and cardiovascular collapse. Several cellular mechanisms have been postulated to explain how propofol alters cardiac contractility and rhythm. Propofol causes bradycardia (as it reduces sympathetic more than parasympathetic tone) and decreased myocardial contractility due to antagonism of beta adrenoreceptors and calcium channels [7,31]. Excess serum fatty acids have pro-arrhythmic effects, and this may explain the ventricular arrhythmias associated with PRIS [44]. Histological studies of the myocardium and skeletal muscle of patients who have died from PRIS showed signs of severe myocytolysis causing cardiac and skeletal muscle rhabdomyolysis [49]. On microscopy, skeletal muscle showed a disorganisation of myofibrils and sarcomeres with an acute necrosis of the muscle fibres (swelling, loss of striations and vacuoles, and degenerate nuclei). Histopathological examination of the heart revealed numerous focal areas of myofibril degeneration surrounded by an acute inflammatory reaction with macrophages and neutrophils [8]. The imbalance between cellular energy production and utilisation in peripheral and cardiac muscle is the key pathogenic mechanism that causes peripheral and cardiac muscle necrosis, and the accumulation of toxic fatty acids. Rhabdomyolysis causes myoglobinuria, acute renal failure and secondary hyperkalaemia [45].

During the publication of the early cases of PRIS, it was suggested that the syndrome may be caused by untreated sepsis; or that metabolic acidosis was a consequence of renal failure and the ensuing arrhythmias were due to acidosis alone [50–52]. Ahlen et al., in a review sponsored by AstraZeneca (the manufacturers of Diprivan), argued that that the cardiovascular features of PRIS could be explained by sepsis and systemic inflammatory response in most of the case reports [53]. In a large number of reports involving patients with head injuries and cerebral oedema, they suggested that the use of fluid restriction and vasopressors were relevant causative factors as these ultimately impaired tissue perfusion. They also suggested the rhabdomyolysis could be explained by inadequate oxygen supply to the skeletal muscle, which leads to anaerobic metabolism and, if severe, causes muscle cell death with rhabdomyolysis and increased serum creatinine levels. Rhabdomyolysis may be associated with the administration of high doses of steroids in some of the case reports.

Hepatomegaly and fatty change associated with PRIS may be mediated by several mechanisms. Bray [5] suggested it is caused by hepatic congestion secondary to cardiac failure. Fat infiltration of organs may be caused by the high lipid content of propofol [5]. Parke et al. proposed that, in critically ill patients, enhanced sympathetic nervous system stimulation, cortisol and growth hormone increased lipolysis and fat oxidation, resulting in a large increase in circulating non-esterified fatty acids [2]. Ahlen et al. [53] suggest that hypoperfusion, hypoxia, sepsis, hypermetabolic states, and vasopressor therapy impair liver function and exacerbate hyperlipidaemia. Normal lipid metabolism in the liver requires carbohydrate substrates. The authors postulated that as a result of depletion of carbohydrate stores in the critically ill patient, lipid accumulation associated with the high propofol infusion rates is not a direct toxicity of propofol but rather a consequence of exhaustion of carbohydrate stores. However, this cannot explain the occurrence of the syndrome in some patients who developed signs of PRIS during a relatively short anaesthetic. The possibility of a genetic predisposition cannot be excluded.

Vasile et al. proposed ‘priming factors’ and ‘triggering factors’ that contribute to PRIS [49]. The ‘priming factors’ include endogenous catecholamines, glucocorticoids, systemic inflammation and cytokine production in critically ill patients [Fig. 4]. High dose propofol and exogenous catecholamines and corticosteroids are the ‘triggering’ factors. In the critically ill patient, endogenous and exogenous catecholamines contribute to cardiac and peripheral muscle injury. Vasile et al. [49] noted that myofibrillar degeneration (or coagulative myocytolysis) in cardiac and skeletal muscle was associated with high blood levels of exogenous and endogenous catecholamines. In addition, catecholamine-induced lipolysis increases the circulating free fatty-acid load, and this compounds the pathology. Steroids may also have a triggering role in acute muscle damage. Several critically ill patients who presented with PRIS received high dose steroids during the treatment in the ICU. It is suggested that steroids induce proteolysis of the cardiac contractile myofilaments.

image

Figure 4.  Factors that predispose to the propofol infusion syndrome. Critical illness or genetic factors may be ‘priming’ factors, and propofol, catecholamines and glucocorticoids are triggering factors that precipitate the systemic disturbances of propofol infusion syndrome.

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Preventing PRIS in the critically ill

  1. Top of page
  2. Summary
  3. Methods
  4. History
  5. Cases recorded
  6. Mechanism of PRIS
  7. Pathophysiological features of PRIS
  8. Preventing PRIS in the critically ill
  9. Early markers of PRIS
  10. Management
  11. References

Carbohydrate stores are depleted more rapidly in children than in adults and this may explain the higher prevalence of PRIS in children. In critically ill patients, an inadequate supply of carbohydrate to the patient promotes the mobilisation of fat stores and increases fat metabolism [43]. This increases the circulating fatty-acid load and predisposes to PRIS. It is suggested that early adequate carbohydrate intake can prevent PRIS by preventing the switch to fat metabolism [27, 46]. Certainly the larger carbohydrate stores in adults may explain the lower incidence of this syndrome in adults. Wolf et al. suggested that a carbohydrate intake of 6–8 mg.kg−1.min−1 can suppress fat metabolism in critically ill children and thus prevent PRIS [27].

A major concern with propofol is the lipid load owing to its formulation. A daily intravenous lipid load of 2–3 g.kg−1.day−1 is regarded as adequate for children on total parenteral nutrition (TPN). This is equivalent to a fat load conferred by a 1% propofol infusion running at 4 mg.kg−1.h−1. As most of the reported cases of PRIS were associated with infusion rates greater than 4 mg.kg−1.h−1, it is postulated that the excessive lipid load may be a contributory factor [43]. The use of a more concentrated propofol solution (60 mg.ml−1) can reduce the lipid load [54].

Early markers of PRIS

  1. Top of page
  2. Summary
  3. Methods
  4. History
  5. Cases recorded
  6. Mechanism of PRIS
  7. Pathophysiological features of PRIS
  8. Preventing PRIS in the critically ill
  9. Early markers of PRIS
  10. Management
  11. References

There is much interest in the identification of an early marker of PRIS. Unexplained metabolic acidosis, elevated serum lactate, creatine kinase and myoglobin levels or hyperlipidaemia may all herald the onset of PRIS. Three case reports suggested that early onset lactic acidosis after the start of propofol infusions in the absence of other causes may be an early marker of PRIS. Koch et al. described the clinical course of a 5-year-old girl who was sedated with high dose propofol infusion in the ICU after embolisation of a cerebral arteriovenous malformation (AVM). She developed lactic acidosis (peak values: lactate 5.3 mmol.l−1, BE − 5.6 mmol.l−1, pH 7.31) 6 h after a propofol infusion was started at 15 mg.kg−1.h−1. The acidosis resolved when propofol was ceased. No other features of PRIS were present [55]. Kill et al. reported that a 7-year-old boy with osteogenesis imperfecta undergoing surgery to the distal femur developed lactic acidosis following a 150-min propofol anaesthetic (mean infusion rate of 13.5 mg.kg−1.h−1) [56]. Haase et al. reported that elevated serum lactate levels (2.7 mmol.l−1) were detected only 1 h after a short 40-min propofol infusion (total dose 6.1 mg.kg−1). The patient had an uneventful general anaesthetic but was transferred to PICU postoperatively. Serum lactate levels peaked at 9.4 mmol.l−1 7 h after admission to PICU, then returned to near normal over the next 10 h [57].

Onur et al. investigated the effect of propofol infusion on acid-base status and liver and myocardial enzyme levels during short-term anaesthesia in children. The only statistically significant findings were a lower pH and higher triglyceride level in the propofol group (p < 0.05). However, the changes were not clinically important [58]. Elevated malonylcarnitine or acylcarnitine levels (C2, 4, or 5) indicate impaired fatty-acid metabolism and may be potential early makers of the onset of PRIS, but these tests are not readily available in most hospital laboratories [27, 43].

Hypertriglyceridaemia is well documented in many PRIS patients [2, 43]. A significant rise in serum triglyceride occurs even in short-term propofol infusions in healthy patients without adverse effects [59]. A role of serum triglycerides as an early marker of PRIS is therefore unlikely. Monitoring serum creatine kinase and myoglobin levels has been suggested but its utility as an early marker of PRIS is questionable [60].

Electrocardiographic changes in a patient receiving a propofol infusion may warn the clinician of an impending PRIS. The development of coved ST elevations in the right praecordial leads (V1 to V3), similar to that seen in the Brugada syndrome, may be the first sign of cardiac instability that is commonly associated with PRIS [38].

Management

  1. Top of page
  2. Summary
  3. Methods
  4. History
  5. Cases recorded
  6. Mechanism of PRIS
  7. Pathophysiological features of PRIS
  8. Preventing PRIS in the critically ill
  9. Early markers of PRIS
  10. Management
  11. References

The successful management of PRIS relies on a prompt recognition of the early signs. The propofol infusion should be stopped and an alternative sedation agent should be used. Cardiorespiratory support and haemodialysis or haemofiltration are required. Conventional circulatory support measures have had limited success in the treatment of patients with PRIS. Many case reports highlight the refractory nature of this condition to intravenous fluid volume support and the use of escalating doses of inotropes [2, 4, 6, 8–10, 12, 24]. Limited success has been achieved with cardiac pacing (both transvenous and external) [2, 12, 27–32]. Two reports have recorded the successful use of extracorporeal membrane oxygenation (ECMO) for oxygenation and circulatory support [31, 32]. Haemodialysis or haemofiltration has been advocated to decrease the blood levels of metabolic acids and lipids, and has been the most effective treatment of severe PRIS when combined with cardiorespiratory support [13, 19, 27–32].

The heterogeneity of the details and the lack of good metabolic and cardiovascular data has made it more difficult to accept PRIS as a distinct clinical entity. There is great uncertainty surrounding PRIS and much debate has been stimulated [33, 60–64]. There are now adequate data that suggest that infusion rate and duration of propofol administration can be relevant factors for the development of the syndrome, especially in critically ill patients treated in the intensive care units. Precautionary statements about propofol use in intensive care [64] and anaesthesia can be made. It is recommended that a propofol infusion rate of greater than 4 mg.kg−1.h−1 for longer than 48 h should be avoided. However, there are reports which indicate that PRIS can occur with high dose infusions of a shorter duration. Early metabolic acidosis has been reported 1–4 h after the commencement of infusion [17, 56], and one patient reportedly developed PRIS after 5 h of infusion [41]. An idiosyncratic reaction or a genetic predisposition must be considered a possibility. Predisposing factors include young age, severe critical illness of central nervous system or respiratory origin, exogenous catecholamine or glucocorticoid administration, inadequate carbohydrate intake and subclinical mitochondrial disease [49]. Future research should be directed at establishing the precise pathophysiological cellular mechanisms of the syndrome, and the identification of a genetic predisposition, so that PRIS can be avoided in susceptible patients.

References

  1. Top of page
  2. Summary
  3. Methods
  4. History
  5. Cases recorded
  6. Mechanism of PRIS
  7. Pathophysiological features of PRIS
  8. Preventing PRIS in the critically ill
  9. Early markers of PRIS
  10. Management
  11. References
  • 1
    Hatch DJ. Propofol-infusion in children. Lancet 1999; 353: 11178.
  • 2
    Parke TJ, Stevens JE, Rice ASC, Greenway CL, Bray RJ, Smith PJ, Waldmann CS, Verghese C. Metabolic acidosis and fatal myocardial failure after propofol infusion in children: five case reports. British Medical Journal 1992; 305: 6136.
  • 3
    Cremer OL, Moons KGM, Bouman EAC, Kruijswijk JE, De Smet AMGA, Kalkman CJ. Long term propofol infusion and cardiac failure in adult head-injured patients. Lancet 2001; 357: 1178.
  • 4
    Hanna JP, Ramundo ML. Rhabdomyolysis and hypoxia associated with prolonged propofol infusion in children. Neurology 1998; 50: 3013.
  • 5
    Bray RJ. Propofol infusion syndrome in children. Paediatric Anaesthesia 1998; 8: 4919.
  • 6
    Badr AE, Mychaskiw G, Eichhorn JH. Metabolic acidosis associated with a new formulation of propofol. Anesthesiology 2001; 94: 5368.
  • 7
    Ernest D, French C. Propofol Infusion Syndrome – report of an adult fatality. Anaesthesia and Intensive Care 2003; 31: 3169.
  • 8
    Stelow EB, Johari VP, Smith SA, Crosson JT, Apple FS. Propofol-associated rhabdomyolysis with cardiac involvement in adults: chemical and anatomic findings. Clinical Chemistry 2000; 46: 57781.
  • 9
    Cannon ML, Glazier SS, Bauman LA. Metabolic acidosis, rhabdomyolysis and cardiovascular collapse after prolonged propofol infusion. Journal of Neurosurgery 2001; 95: 10536.
  • 10
    Perrier ND, Baerga-Varela Y, Murray MJ. Death related to propofol use in an adult patient. Critical Care Medicine 2000; 28: 30714.
  • 11
    Baumeister FA, Oberhoffer R, Liebhaber GM, et al. Fatal propofol infusion syndrome in association with ketogenic diet. Neuropaediatrics 2004; 35: 2502.
  • 12
    Holzki J, Aring C, Gillor A. Death after re-exposure to propofol in a 3-year old child: a case report. Paediatric Anaesthesia 2004; 14: 26570.
  • 13
    Casserly B, O'Mahony E, Timm EG, Haqqie S, Eisele G, Urizar R. Propofol Infusion Syndrome: an unusual cause of renal failure. American Journal of Kidney Diseases 2004; 44: 98101.
  • 14
    Kelly DF. Propofol Infusion Syndrome. Journal of Neurosurgery 2001; 95: 9256.
  • 15
    Friedman JA, Manno E, Fulgham JR. Propofol. Journal of Neurosurgery 2002; 96: 11612.
  • 16
    Burow BK, Johnson ME, Packer DL. Metabolic acidosis associated with propofol in the absence of other causative factors. Anesthesiology 2004; 101: 23941.
  • 17
    Salengros JC, Velghe-Lenelle CE, Bollens R, Engelman E, Barvals L. Lactic acidosis during propofol–remifentanil anaesthesia in an adult. Anesthesiology 2004; 101: 2413.
  • 18
    Liolios A, Guerit JM, Scholtes JL, Raftopoulous C, Hanston P. Propofol Infusion Syndrome with short-term large-dose infusion during surgical anaesthesia in an adult. Anesthesia and Analgesia 2005; 100: 18046.
  • 19
    Machata AM, Gonano C, Birsan T, Zimpfer M, Spiss CK. Rare but dangerous adverse effects of propofol and thiopental in intensive care. Journal of Trauma, Injury, Infection and Critical Care 2005; 58: 6435.
  • 20
    Kumar MA, Urrutia VC, Thomas CE, Abou-Khaled KJ, Schwartzman RJ. The syndrome of irreversible acidosis after prolonged propofol infusion. Neurocritical Care 2005; 3: 2579.
  • 21
    Chukwuemeka A, Ko R, Ralph-Edwards A. Short-term low-dose propofol anaesthesia associated with severe metabolic acidosis. Anaesthesia and Intensive Care 2006; 34: 6515.
  • 22
    De Waele JJ, Hoste E. Propofol infusion syndrome in a patient with sepsis. Anaesthesia and Intensive Care 2006; 34: 6767.
  • 23
    Corbett SM, Moore J, Rebuck JA, Rogers FB, Greene CM. Survival of propofol infusion syndrome in a head-injured patient. Critical Care Medicine 2006; 34: 247983.
  • 24
    Bray RJ. Fatal myocardial failure associated with a propofol infusion in a child. Anaesthesia 1995; 50: 94.
  • 25
    Strickland RA, Murray MJ. Fatal metabolic acidosis in a paediatric patient receiving an infusion of propofol in the intensive care unit: Is there a relationship? Critical Care Medicine 1995; 23: 4059.
  • 26
    Plotz FB, Waalkens HJ, Verkade HJ, Strengers JLM, Knoester H, Mandema JM. Fatal side effects of continuous propofol infusion in children may be related to malignant hyperthermia. Anaesthesia and Intensive Care 1996; 24: 724.
  • 27
    Wolf A, Weir P, Segar P, Stone J, Shield J. Impaired fatty acid oxidation in propofol infusion syndrome. Lancet 2001; 357: 6067.
  • 28
    Barclay K, Williams AJ, Major E. Propofol infusion syndrome in children. British Medical Journal 1992; 305: 953.
  • 29
    Cray SH, Robinson BH, Cox PN. Lactic acidaemia and bradyarrhythmia in a child sedated with propofol. Critical Care Medicine 1998; 26: 208792.
  • 30
    Withington DE, Decell MK, Al Ayed T. A case of propofol toxicity: further evidence for a causal mechanism. Pediatric Anaesthesia 2004; 14: 5058.
  • 31
    Culp KE, Augoustides JG, Ochroch AE, Milas BL. Clinical management of cardiogenic shock associated with prolonged propofol infusion. Anesthesia and Analgesia 2004; 99: 2216.
  • 32
    Abrahams JM, Reiter GT, Acker MA, Sinson GP. Propofol. Journal of Neurosurgery 2002; 96: 11601.
  • 33
    Van Straaten EA, Hendriks JJE, Ramsey G, Vos GD. Rhabdomyolysis and pulmonary hypertension in a child, possibly due to long-term high-dose propofol infusion. Intensive Care Medicine 1996; 22: 997.
  • 34
    Cornfield DN, Tegtmeyer K, Nelson MD, Milla CE, Sweeney M. Continuous propofol infusion in 142 critically ill children. Pediatrics 2002; 110: 117781.
  • 35
    Markovitz BP. Continuous propofol infusion in 142 critically ill children. Pediatrics 2003; 112: 14601.
  • 36
    Felmet K, Nguyen T, Clark RS, Orr D, Carcillo J. The FDA warning against prolonged sedation with propofol in children remains warranted. Pediatrics 2003; 112: 10023.
  • 37
    Marinella MA. Lactic acidosis associated with propofol. Chest 1996; 109: 292.
  • 38
    Vernooy K, Delhaas T, Cremer OL, et al. Electrocardiographic changes predicting sudden death in propofol-related infusion syndrome. Heart Rhythm 2006; 3: 1317.
  • 39
    Davis R, Bysani K. Lactic acidosis as presenting symptom of propofol infusion syndrome. Pediatric Critical Care Medicine 2005; 6: 629.
  • 40
    Anonymous. Propofol: danger of prolonged and high infusion rates in ICU. Australian Adverse Drug Reactions Bulletin 2004; 23: 234.
  • 41
    Mehta N, De Hunter C, Parviz H, Nadel S, Britto J. Short term propofol infusions in children. Lancet 1999; 354: 8667.
  • 42
    Schenkman KA, Yan S. Propofol impairment of mitochondrial respiration in isolated perfused guinea pig hearts determined by reflectance spectroscopy. Critical Care Medicine 2000; 28: 1727.
  • 43
    Wolf AW, Potter F. Propofol infusion in children: when does an anesthetic tool become an intensive care liability? Paediatric Anaesthesia 2004; 14: 4358.
  • 44
    Jouven X, Charles MA, Desnos M. Ducimetiere P. Circulating nonesterified fatty acid level as a predictive risk factor for sudden death in the population. Circulation 2001; 104: 75661.
  • 45
    Walsh RJ, Amato AA. Toxic myopathies. Neurologic Clinics 2005; 23: 397428.
  • 46
    Short TG, Young Y. Toxicity of intravenous anesthetics. Best Practice and Research in Clinical Anaesthesiology 2003; 17: 7789.
  • 47
    Steiner LA, Studer W, Baumgartner ER, Frei F. Perioperative management of a child with very-long chain acyl-coenzyme A dehydrogenase deficiency. Paediatric Anaesthesia 2002; 12: 18791.
  • 48
    Farag E, DeBoer G, Cohen BH, Niezgoda J. Metabolic acidosis due to propofol infusion. Anesthesiology 2005; 102: 6978.
  • 49
    Vasile B, Rasulo F, Candiani A, Latronico N. The pathophysiology of propofol infusion syndrome: a simple name for a complex syndrome. Intensive Care Medicine 2003; 29: 141725.
  • 50
    Cook S. Propofol infusion syndrome in children. British Medical Journal 1992; 305: 952.
  • 51
    Sulsa GM. Propofol toxicity in critically ill pediatric patients: Show us the proof. Critical Care Medicine 1998; 26: 195960.
  • 52
    Reed MD, Blumer JL. Propofol bashing: The time to stop is now. Critical Care Medicine 1996; 24: 1757.
  • 53
    Ahlen K, Buckley CJ, Goodale DB, Pulsford AH. The ‘propofol infusion syndrome’: the facts, their interpretation and implications for patient care. European Journal of Anaesthesiology 2006; 23: 9908.
  • 54
    Knibbe CAJ, Naber H, Aarts LPHJ, Kuks PFM, Danhof M. Long term sedation with propofol 60mg/ml vs. propofol 10mg/ml in critically ill, mechanically ventilated patients. Acta Anaesthesiologica Scandinavica 2004; 48: 3027.
  • 55
    Koch M, De Backer D, Vincent JL. Lactic acidosis: an early marker of propofol infusion syndrome? Intensive Care Medicine 2004; 30: 522.
  • 56
    Kill C, Leonhardt A, Wulf H. Lactic acidosis after short-term infusion of propofol for anaesthesia in a child with osteogenesis imperfecta. Paediatric Anaesthesia 2003; 13: 8236.
  • 57
    Haase R, Sauer H, Eichler G. Lactic acidosis following short-term propofol infusion may be an early warning of Propofol Infusion Syndrome. Journal of Neurosurgical Anesthesiology 2005; 17: 1223.
  • 58
    Onur O, Asuman Ozkara A, Eris S, Ocal T. Propofol anaesthesia and metabolic acidosis in children. Paediatric Anaesthesia 2003; 13: 537.
  • 59
    Gottschling S, Meyer S, Krenn T, Kleinschmidt S, Reinhard H, Graf N, Shamdeen GM. Effects of short-term propofol administration on pancreatic enzymes and triglyceride levels in children. Anaesthesia 2005; 60: 6603.
  • 60
    Coetzee JF, Coetzer M. Propofol in paediatric anaesthesia. Current Opinion in Anesthesiology 2003; 16: 28590.
  • 61
    Kang TM. Propofol infusion syndrome in critically ill patients. Annals of Pharmacotherapy 2002; 36: 14536.
  • 62
    Pulsford AH. Propofol infusion syndrome in critically ill patients. Annals of Pharmacotherapy 2003; 37: 594.
  • 63
    Okamoto MP, Kawaguchi DL, Alpesh NA. Evaluation of propofol infusion syndrome in pediatric intensive care. American Journal of Health-System Pharmacists 2003; 60: 200714.
  • 64
    Crozier TA. The ‘propofol infusion syndrome’: myth or menace? European Journal of Anaesthesiology 2006; 23: 9879.