A Placebo Controlled Trial Of L-Tryptophan In Post-Operative Delirium

• Incidence of post-operative delirium [ Time Frame: post-operatively in ICU ] [ Designated as safety issue: No ]

  The incidence and/or duration of excitatory (hyperactive and mixed) post-operative delirium, diagnosed by the Confusion Assessment Method-ICU (CAM-ICU) with the Richmond Agitation Sedation Score (RASS), will be reduced with enteral L-tryptophan supplementation (1 gm TID for the first 3 post-op days), compared to placebo, in older patients (≥ 60 years) undergoing operations requiring ICU admission.

  The incidence and/or duration of all types of post-operative delirium, diagnosed by the CAM-ICU with the RASS, will be reduced with enteral L-tryptophan supplementation (1 gm TID for the first 3 post-op days), compared to placebo, in older patients (≥ 60 years) undergoing operations requiring ICU admission.

• Level of post-operative serum tryptophan [ Time Frame: post-operative day number two blood draw ] [ Designated as safety issue: No ]
• level of post-operative serotonin and melatonin [ Time Frame: Blood draw on post-operative day number two ] [ Designated as safety issue: No ]
• Length of post-operative ICU and hospital stay [ Time Frame: length of post-op ICU and hospital stay ] [ Designated as safety issue: No ]

• Incidence of post-operative delirium [ Time Frame: post-operatively in ICU ] [ Designated as safety issue: No ]
• Level of post-operative serum tryptophan [ Time Frame: post-operative day number two blood draw ] [ Designated as safety issue: No ]
• level of post-operative serotonin and melatonin [ Time Frame: Blood draw on post-operative day number two ] [ Designated as safety issue: No ]
• Length of post-operative ICU and hospital stay [ Time Frame: length of post-op ICU and hospital stay ] [ Designated as safety issue: No ]

Post-operative delirium is a common and deleterious complication in elderly patients. The investigators have previously found lower levels of serum tryptophan in post-operative elderly patients who developed delirium in comparison to post-operative elderly patients who did not develop delirium. The investigators hypothesize that post-operative supplementation of L-tryptophan will reduce the duration and incidence of post-operative delirium. This study is a double-blinded placebo controlled trial of L-tryptophan supplementation in post-operative ICU patients 60 years and older. The primary outcome measure is the comparison of duration of post-operative delirium in subjects who receive L-tryptophan supplementation versus a similar appearing control.

• Drug: L-tryptophan supplementation
  L-tryptophan 1 gram enterally TID for a maximum of nine doses or to be discontinued at the time of discharge from the ICU (whichever occurs first)
• Drug: placebo
  Similar appearing placebo administered post-operatively (1 enterally TID) for a total of nine doses or discharge from ICU (whichever occurs first)

• Experimental: L-Tryptophan
  L-tryptophan supplementation (1 gram enterally TID) starting post-operatively and continuing for a maximum of 9 doses or the time of discharge from ICU (whichever occurs first)
  Intervention: Drug: L-tryptophan supplementation
• Placebo Comparator: Placebo
  Similar appearing placebo administered post-operatively (1 enterally TID) for a total of nine doses or discharge from ICU (whichever occurs first)
  Interventions:

  • Drug: L-tryptophan supplementation
  • Drug: placebo

• Robinson TN, Raeburn CD, Angles EM, Moss M. Low tryptophan levels are associated with postoperative delirium in the elderly. Am J Surg. 2008 Nov;196(5):670-4. Epub 2008 Sep 11.
• Robinson TN, Raeburn CD, Tran ZV, Angles EM, Brenner LA, Moss M. Postoperative delirium in the elderly: risk factors and outcomes. Ann Surg. 2009 Jan;249(1):173-8.

Inclusion Criteria:

• Included subjects will be 60 years and older undergoing an operation with a planned ICU admission post-operatively.

Exclusion Criteria:

• Medications that, when combined with tryptophan, increase the risk of serotonin syndrome. The classes of medications include:

  • monoamine oxidase inhibitors
  • selective serotonin reuptake inhibitors
  • serotonin-norepinephrine reuptake inhibitors
  • triptans
  • opioids
  • central nervous system stimulants
  • bupropion
  • St. John's Wort
• Patients who undergo an operation on their brain.
• Factors which prevent delirium assessment with the CAM-ICU: vision impairment or non-fluent English speakers.

• A lowered seizure threshold including:

  • history of seizure disorder
  • alcohol abuse defined by a high AUDIT score (>8 females and >13 males)
  • benzodiazepine or barbiturate abuse within three months of the study
  • OR a positive urine toxicology screen for alcohol, benzodiazepines or barbiturates.
• Significant liver disease (Child's class B or greater) or significant renal disease (Creatinine ≥2.0).
• History of Huntington's or Addison's disease. (As requested by the FDA)
• History of bipolar disorder or a psychotic disorder (such as a psychotic major depression, schizophrenia, schizoaffective disorder, or psychosis in Alzheimer's disease or other dementia). (As requested by the FDA)
• Women who are not post-menopausal. (As requested by the FDA)