Effect Of Exogenous Melatonin on the Incidence of Delirium and Its Association with Severity of Illness in Postoperative Surgical ICU Patients

Dr. Kriti Gupta, MD

Dr. Vipin K. Singh, MD

Dr. Zia Arshad, MD*

Dr. G. P. Singh, MD

*Corresponding Author

Department of Anaesthesiology

King George’s Medical University

Lucknow UP, India 226003

Abstract 

Background: Delirium is common in critically ill intensive care unit (ICU) patients and has been documented in up to 87 percent of patients. Sleep deprivation and delirium have been associated. Alteration of melatonin production has been associated with delirium. Melatonin acts via melatonin receptors present in the suprachiasmatic nuclei (SCN) and promotes sleep by attenuating the wake-promoting signal from the SCN.

Objective: To determine the relationship between exogenous melatonin and the incidence of delirium and its association of with severity of illness, measured in term of APACHE II, procalcitonin level at the time of admission and daily SOFA score.

Patients and Methods:

Design: Randomised placebo-control study.

Setting: the study was conducted in critical care setting in a tertiary level ICU.

Participants: Postoperative patients age between 20-60 years who are going to be ventilated more than 48 hours without any contraindication to enteral medications.

Interventions: Study group received melatonin 5 mg through the enteral route.

Main outcome measures: To determine the effect of exogenous melatonin on the incidence of delirium in postoperative patients who require mechanical ventilation for more than 24 hours. The secondary outcome measures are procalcitonin (PCT) value at admission and disease severity scores like APACHE II and SOFA.

Results: No statistically significant difference was found in admission incidence of delirium or procalcitonin. Age was higher in those patients that developed delirium (p < 0.05).

Conclusions: Although the incidence of delirium is not affected by exogenous melatonin or higher APACHE scores, it had a significant correlation with higher procalcitonin, that in turn indicated an association with delirium and sepsis. It was found that there is increased risk of developing delirium with increasing age.

Key words: delirium, intensive care unit, sedation, melatonin, APACHE II, procalcitonin,

Introduction

Delirium is defined as “A disturbance in attention (i.e., reduced ability to direct, focus, sustain and shift attention) and awareness (reduced orientation to the environment)” (1). Delirium is extremely prevalent in hospitalized patients; it affects 10%–24% of the adult general medicine population and 37–46% of the general surgical population. Delirium has been documented in up to 87 percent of patients in the intensive care unit (ICU) (2). Multiple etiologies have been hypothesized to be causing delirium. Some of these are central cholinergic deficiency, reduced GABA activity, abnormal serotonin and melatonin pathways, cerebral hypo perfusion and neuronal damage due to inflammation (3,4). Acute Physiology and Chronic Health Evaluation II score (APACHE II) and the Sequential Organ Failure Score (SOFA) score have been found to aid in the prediction of delirium in the critically ill.

It has been demonstrated that pattern of secretion and concentration of melatonin are altered in critically ill patients (5). Melatonin release from the pineal gland is also decreased due to surgical stress and hence its potential use in postoperative delirium (6). Sepsis-associated delirium is a cerebral manifestation commonly occurring in patients with other infection-related organ dysfunctions and is caused by a combination of neuroinflammation and disturbances in cerebral perfusion (7). Procalcitonin is a helpful biomarker for early diagnosis of sepsis in critically ill patients (8).

Melatonin acts via melatonin receptors present in the suprachiasmatic nuclei (SCN) and promotes sleep by attenuating the wake-promoting signal from the SCN (9,10). Bioavailability of melatonin is excellent as demonstrated by supraphysiological level after exogenous supplementation (11).

The Confusion Assessment Method (CAM) is a diagnostic instrument used to screen and diagnose delirium in ICU. The CAM diagnostic algorithm is comprised of four components: (1) an acute (4) an altered level of consciousness. The diagnosis of delirium is based on the presence of both component 1 and 2, and either 3 and 4 (12).

Objective

The primary objective of the study was to determine the efficacy of exogenous melatonin in preventing delirium in postoperative patients admitted in ICU, as well as to compare the outcome by comparing the incidence of delirium and length of ICU stay in two groups. The secondary objective is to determine the association of delirium with severity of illness, which was measured in term of APACHE II and Procalcitonin level at the time of admission and daily SOFA scoring.

Methods

We performed a randomized, placebo-controlled study on postoperative patients admitted in our 20-bed tertiary level ICU. Inclusion criteria included adult postoperative patients requiring mechanical ventilation for more than 48 hours who were able to receive medication by the enteral route. Exclusion criteria included unwillingness to participate; sensitivity or history of allergic reaction to melatonin supplements; pregnancy; paralytic ileus; patients not expected to survive >48 hours; preexisting pathologies including cognitive dysfunction, dementia, psychiatric disorders or sleep disorders; history of head injury, substance abuse or withdrawal; and patients with hearing impairments.

Patients were randomized into two groups of 70 patients each with a sealed envelope randomization method. The study group received melatonin 5 mg via the enteral route at 8 pm every day and the control group received placebo (1 gm lactose powder) through a nasogastric tube until ICU discharge/transfer. APACHE II and procalcitonin (PCT) levels were recorded at admission, and SOFA scores were calculated daily. Delirium preventive measures including decreased light, noise, and regular patient orientation were applied uniformly in both groups. On the day of discharge/transfer the patients were evaluated using the CAM-ICU (Confusion Assessment Method) scale. The patients were categorized as “Delirious” or “Not Delirious” on the basis of the results from the CAM-ICU scale (12). Results were analyzed by comparing the incidence of delirium, length of ICU stay, APACHE II, SOFA Score and PCT value at the time of admission.

Results

A total of 140 adult post-operative patients transferred to the ICU who were ventilated more than 48 hours were evaluated. Table 1 contains the demographics of the study population.

Table 1: Between Group Comparison of Demographic Profile

Mean age of patients enrolled in the study was 38.70±11.56 years. Difference in age of patients in Group A (38.46±11.87) and Group B (38.94±11.33) was not statistically significant.

APACHE II scores did not differ at admission (Table 2).

Table 2: Between Group Comparison of APACHE II Score

Procalcitonin levels did not differ at admission (Table 3).

Table 3: Between Group Comparison of Procalcitonin (ng/ml)

Range of procalcitonin levels of patients of both the groups was 0.2-25.60 ng/ml. Though mean procalcitonin levels of patients of Group B (5.76±6.37 ng/ml) were found to be higher than that of Group A (4.81±6.60 ng/ml) yet this difference was not found to be significant statistically.

Duration of ICU stay was 4 to 27 days. Though mean ICU stay of patients of Group A (9.29±4.57 days) was higher than that of Group B this difference was not found to be significant statistically.

SOFA score of 56 patients of Group A and 55 patients of Group B could be assessed. Median SOFA score of patients of both the groups was 2.00, mean SOFA score of patients of Group A was 2.70±2.20 (range 0-9) while that of Group B was 2.53±1.63. On comparing SOFA score of patients of above two groups, difference was not found to be significant statistically.

CAM ICU score of 111 patients could be assessed. The majority of overall (68.5%) as well as Group A (76.8%) and Group B (60.0%) had negative CAM ICU scores. Though a higher proportion of Group B as compared to Group A had a positive CAM ICU score (40.0% vs. 23.2%), this difference was not found to be significant statistically.

There was no significant difference in the mortality of non-delirious patients.

Patients with delirium as compared to non-delirium had significantly higher values of APACHE-II (20.57±6.26 vs. 18.42±7.14) and significantly higher procalcitonin levels (5.84±6.25 vs. 3.42±6.57 ng/ml).

Table 4: Association of Delirium with Demographic Profile

 

Patients with delirium were found to be older as compared to non-delirium (41.57±9.99 vs. 35.87±11.81). This difference was found to be significant statistically. Proportion of females was higher among delirious as compared to non-delirious patients (54.3% vs. 47.4%), but this difference was not found to be significant statistically.

Delirium was less prevalent in Group A (16.6 percent) than Group B (31.4 percent), although the difference was not statistically significant. Melatonin administration did not significantly affect any of the other outcomes (p>0.05, all comparisons).

Discussion

Delirium is prevalent in all spheres of hospitalization, medical and surgical patients, more prominently in patients admitted to intensive care units. Owing to its multifactorial etiopathogenesis, multiple pharmacological and non-pharmacological methods have been described in various literatures for prevention and treatment of delirium.

Delirium is associated with various complications which may result in unfavorable outcomes. These complications may vary from minor complications like self-extubation, removal of catheters, weaning failure, increase length of ICU stay to increased mortality. Ely and coworkers(13) studied 275 mechanically ventilated medical ICU patients and determined that delirium was associated with a threefold increase in risk for 6-month mortality after adjusting for age, severity of illness, co-morbidities, coma, and exposure to psychoactive medications. The commonest factors significantly associated with delirium are dementia, increased age, co-morbidities, severity of illness, infection, decreased day to day activities, immobilisation, sensory disturbance, urinary catheterization, urea and electrolyte imbalance and malnutrition (14).

Frisk et al. (15) in 2004 conducted a study to assess the biochemical indicators of circadian rhythm of patients admitted in ICUs and found altered secretion patterns and reduction in the urinary metabolite of melatonin, 6-SMT (6-sulphatoxymelatonin). This indicated the possible disruption of this neurohormone in patients admitted in intensive care units. Andersen et al. (16)  concluded that exogenous melatonin could be utilized to alleviate preoperative anxiety in surgical and critical care patients and more importantly, to decrease the emergence of delirium in the early postoperative period. In our study, 140 adult post-operative patients were studied to establish the preventive role of melatonin in delirium. Aghakouchakzadeh et al. (17)  in 2017 conducted a comprehensive review to determine the effect of melatonin on delirium; they concluded that because exogenous melatonin can improve circadian rhythm and prevent delirium, melatonin supplementation could improve or manage delirium in the intensive care unit. Similarly, Yang et al. (18) in their review had found substantial preventative effects of melatonin on delirium .This investigation established a reason for the practice recommendations to recommend melatonergic medications for delirium prevention.

Out of 140 patients that we studied, 29 patients died during the trial, 35 were diagnosed with delirium and 76 had no delirium. Delirium was less prevalent in Group A (16.6 percent) than Group B (31.4 percent), although the difference was not statistically significant. This reduction is similar to the results found by Nishikimi et al. (19) in who found the melatonin agonist to be related to a trend toward shorter ICU stays, as well as significant reductions in the occurrence and duration of delirium in patients admitted to the ICU.

Sepsis and inflammation are important etiologies of delirium. Inflammatory biomarkers (procalcitonin and erythrocyte sedimentation rate) can be predictive of acute brain dysfunction and delirium. Hamza et al.  (20) procalcitonin was significantly higher in their delirious group in univariant (0.9±0.6 vs. 0.4±0.4ng/mL, P<0.001) and multivariate analysis (OR= 35.59, CI (7.73- 163.76)). Similarly, McGrane S et al. (21) conducted a study in 87 non-intensive care unit (ICU) cohorts and found that higher levels of procalcitonin were associated with fewer delirium/coma-free days (odds ratio (OR), 0.5; 95% confidence interval (CI), 0.3 to 1.0; P = 0.04). Our study showed similar results with significantly higher procalcitonin levels in patients with delirium than those without delirium (5.84±6.25 vs. 3.42±6.57 ng/ml).

The Acute Physiology and Chronic Health Evaluation II score (APACHE II) provides a classification of severity of disease and is particularly used in the ICU to predict mortality. In our study, APACHE II scores were calculated for each patient at their admission in the ICU. The range of APACHE-II score of patients enrolled was 6 to 38. Patients of Group A and Group B had comparable APACHE-II Score (21.07±8.17 vs. 21.84±7.81). Patients with delirium as compared to non-delirium had higher values APACHE-II scores (20.57±6.26 vs. 18.42±7.14). This was similar to the findings of Hamza SA et. al.(17), who, in their observational study of 90 patients, found not only have higher APACHE scores but also that the APACHE-II scores had significantly high diagnostic performance in discrimination of delirium (AUC = 0.877, P= <0.001).

Another clinically important score is the Sequential Organ Failure Score (SOFA) score used to sequentially assess the severity of organ dysfunction in critically ill patient ,  is an objective score that calculates the number and the severity of organ dysfunction in six organ systems (respiratory, coagulation , liver, cardiovascular, renal, and neurologic). In a prospective cohort study on 400 consecutive patients admitted to the ICU Rahimi-Bashar et al. (22) found the SOFA scores were significantly higher in those with delirium (7.37 ± 1.17) than those without delirium (4.93 ± 1.70). Similarly in our study, SOFA score of patients with delirium (4.49±1.63) was found to be significantly higher than that of non-delirium (1.75±1.37). Hence the elevated SOFA and APACHEII scores in the delirium can assist in identifying at-risk patients for delirium and hence allow interventions to improve outcomes. 

Aging is often associated with a disruption of the normal circadian cycle, which can also result in delirium. Thus, melatonin and its agonist may have a more significant influence on delirium in the elderly than in the young, Abbasi et al. (23) discovered that delirium is uncommon in a relatively young group. Thus, the relatively young age of our study sample and the enhancement of ICU care (such as decreased light, noise, and regular patient orientation) are the primary reasons for our study's low prevalence of delirium. Additionally, we found patients with delirium were older as compared to non-delirium (41.57±9.99 vs. 35.87±11.81).

As previously stated, the potential benefit of exogenous melatonin supplementation in reducing delirium incidence has been evaluated in non-ICU settings as well. While both the Sultan (24) and Jonghe (25) investigations examined whether melatonin may help postoperative patients avoid delirium, the de Jonghe study employed six times the amount of melatonin used in the Sultan study (3 mg versus 0.5 mg, respectively).

We suggest that individuals at risk of developing delirium, such as the elderly, should be investigated in future researches. Also, further studies are required comparing subgroups of medical, surgical, and trauma patients to determine which patients will benefit most from exogenous melatonin administration. Because plasma and urinary levels of melatonin are directly related to its concentration in the central nervous system, we also recommend monitoring melatonin levels in plasma or urine during the study and for follow-up to ascertain which subgroup of patients benefited most from exogenous melatonin supplementation to prevent delirium.

Conclusion

The study demonstrates there is decreased incidence of delirium in the patients who received exogenous melatonin, although this difference was statistically not significant (p=0.057). There was a statistically significant association of age with development of delirium (p=0.015). It has also been observed that the higher procalcitonin levels are associated with increased incidence of delirium (<0.001).

References

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Cite as: Gupta K, Singh VK, Arshad Z, Singh GP. Effect Of Exogenous Melatonin on the Incidence of Delirium and Its Association with Severity of Illness in Postoperative Surgical ICU Patients. Southwest J Pulm Crit Care Sleep. 2022;25(2):7-14. doi: https://doi.org/10.13175/swjpcc030-22 PDF 

Brief Review: Delirium

Evan D. Schmitz, MD

Jack B. Vu, MD

University of Washington

Seattle, WA

A significant number of patients develop a decline in cognitive function while hospitalized. Delirium in the intensive care increases mortality and healthcare costs and should be recognized and treated promptly (1,2). 

This is a brief review of delirium and important treatment options such as early percutaneous tracheostomy, neuroleptics, propofol, daily awakenings and reorientation by all team members. We recommend neither neuroimaging nor neurology consultation unless physical exam suggests an acute cerebral vascular accident or status epilepticus as the majority of these patients require no neurologic intervention and may be harmed by transportation to obtain additional testing.

The DSM-5 defines delirium as a disturbance in attention (reduced ability to direct, focus, sustain, and shift attention) and awareness (reduced orientation to the environment). The disturbance develops over a short period of time (usually hours to a few days), represents a change from baseline attention and awareness, and tends to fluctuate in severity during the course of a day. Delirium may also be a disturbance in cognition (memory deficit, disorientation, language, visual spatial ability, or perception).

The leading cause of delirium in the intensive care unit is metabolic encephalopathy caused by the patient’s primary disease and exacerbated by treatment with life saving measures such as intubation with mechanical ventilation. The required anesthesia and analgesia during intubation contribute to worsening delirium. The quicker the patient is extubated, the better is the overall prognosis. Delirium makes it more difficult to extubate the patient, independent of the disease process as the clinician is uncertain if the patient will be able to protect their airway and breathe on their own. This is further compounded by the increasing need for nursing during this critical period. There are numerous studies showing the benefits of sedation vacation and reorientation by nursing. If you were to speak with nurses they will tell you how difficult it is dealing with a delirious patient as the patient can become combative and difficult to console. As hospitals continue to cut back on nurses, nursing aids, respiratory therapists and sitters, it becomes increasingly more difficult to care for these patients.

Nursing is one of the most dangerous careers according to the U.S. Bureau of Labor (3). Delirium is directly responsible for traumatic injuries nurses suffer from combative patients while caring for the critically ill. It is therefore understandable why a majority of nurses are concerned when they are told to extubate these delirious patients.

We make it a point to educate nurses that they should extubate the patient as soon as possible. Once a plan is established, including neuroleptics to control agitation, it is important that the physician conducts bed rounds on the patient multiple times during the day. The physician should also explain to the nocturnal staff the importance of avoiding re-intubation, as these delirious patients do respond to neuroleptics and redirection. We only recommend extubation if the whole team is on board.

We have been performing percutaneous tracheostomies since 2006 and have noticed a significant decrease in ventilator days and duration of delirium in those patients receiving this surgery. Once a percutaneous tracheostomy is placed, a patient can be ventilated with minimal or no sedatives which allows improvement in their cognitive function.

Immediately after paralytics have worn off after performing a bedside percutaneous tracheostomy, we stop all sedatives and narcotics to allow the patient to regain consciousness. We use neuroleptics to treat delirium while awaiting for the return of cognitive function. With a tracheostomy in place, the respiratory therapists and nurses appear much more comfortable allowing patients to recover without giving any narcotics or sedatives resulting in a much faster recovery. Patients with neurological impairment, including delirium, demonstrate tachypnea out of proportion to their respiratory needs. Recognition of this type of breathing pattern is important. Educating the staff about this type of breathing pattern also helps nurses and respiratory therapists to cope with the resultant high minute ventilation. If there are periods of apnea with irregular periods of hyperventilation, the breathing pattern is called Biot’s breathing (4).

Once placed, percutaneous tracheostomy as opposed to endotracheal intubation, requires neither anesthetic nor analgesic. Since the tracheostomy is usually placed between the first and second tracheal cartilaginous rings, the vocal cords are free from damage including swelling that occurs with endotracheal tubes. Endotracheal tubes are very uncomfortable and analgesia and anesthesia are required to keep patients comfortable. This can cause delirium. The incidence of tracheal stenosis does not appear to be greater with percutaneous tracheostomy as opposed to endotracheal intubation.

Percutaneous tracheostomy can be performed safely at the bedside in the intensive care unit. As long as one physician is controlling the airway while performing direct visualization via bronchoscopy and the other is performing the percutaneous tracheostomy, any adverse complications can be managed promptly. Remember to place a sign in the patient’s room warning staff not to replace the tracheostomy if it were to fall out within the first seven days and to call a code for prompt intubation. This will avoid misplacement which can lead to death.

Although we are not recommending tracheostomy just for the treatment of delirium, we do recommend early tracheostomy within a few days as opposed to waiting to perform a tracheostomy when anticipated ventilation is longer than ten days. Most of our colleagues who perform percutaneous tracheostomy agree (Schmitz ED, unpublished observations.

Haloperidol (Haldol®) has been around for decades. Haloperidol is a butyrophenone antipsychotic which acts primarily by blocking postsynaptic mesolimbic dopaminergic D2 receptors in the brain. This results in depression of the reticular activating system (5).

As opposed to sedatives and analgesics, haloperidol does not suppress intellectual function or cause respiratory failure. It appears underutilized because of concern about prolonging the QT interval and increasing the risk for a cardiac arrhythmia (6). Although it is true that neuroleptics can prolong the QT interval, the fear associated with this rare phenomenon inhibits the use of the most effective treatment for delirium we have at our disposal. 

Newer antipsychotics such and olanzapine, risperidone and ziprasidone may be used as well, but they also have been associated with inducing cardiac arrhythmias. These drugs appear to have less extrapyramidal side effects caused by the excitatory actions of unopposed cholinergic neurons. These newer antipsychotics block the serotonin receptor 5HT and to a lesser extent D2, and therefore, they decrease the likelihood of acute dystonic reactions, pseudo-parkinsonism, akathisia and tardive dyskinesia (7).

We have had great success with intravenous haloperidol. We recommend starting with a 5-10 mg intravenously and repeating this dose every 15 minutes until the patient’s agitation is controlled. We then schedule haloperidol intravenously as needed. Depending on which newer neuroleptics are available, we schedule these drugs until the patient recovers from their delirium. We have also had success with sublingual or intramuscular olanzapine 10 mg every 8 to 12 hours. Much higher doses, greater than 200 mg a day, have been reported in hospice patients without adverse cardiac effects (8).

Prior to instituting neuroleptics, ensure that the patient’s electrolytes are normal which will decrease the likelihood of an arrhythmia. Try to avoid haloperidol in patients with Parkinson’s disease because it diminishes the availability of dopamine.

An additional measure to decrease the risk and length of delirium is by using propofol and fentanyl for sedation rather than a benzodiazepine. Recent studies have shown that using propofol instead of a benzodiazepine decreases mortality, ventilator days and delirium (9). The elderly and those with liver impairment appear to benefit the most from propofol because of the faster metabolism of this class of drug. Side effects such as hypotension can be easily managed with fluids and a low dose of norepinephrine.

Renal failure is common in critically ill patients. It is important to monitor patients closely for signs of uremic encephalopathy which occurs when patients are unable to adequately excrete nitrogenous waste and other factors (10).

Nitrogen is excreted by the kidneys as urea and ammonium. Amino acids are catabolized by transamination which is the process of transferring their alpha-amino group to alpha-ketoglutarate which produces glutamate. The two most important are alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Alpha-ketoglutarate is an essential intermediate substrate in the citric acid cycle (11).

Glutamate can be oxidized to form free ammonia or it can combine with ammonium in the presence of ATP to form glutamine in the muscle, liver and nervous system providing a nontoxic storage and transport form of ammonia. 

In renal failure hyperammonemia occurs leading to tremors, slurring of speech and blurring of vision. In the presence of elevated ammonia, alpha-ketoglutarate combines with ammonia to form glutamate. Glutamate accumulates which causes cytotoxicity to nerve cells and death via NMDA-type synapses which mediate calcium influx (5). As the concentration of alpha-ketoglutarate declines, the brain cannot produce the energy it needs through the citric acid cycle which can lead to coma and death.

Although drugs used to treat hyperammonemia in patients with liver failure such as neomycin, lactulose and rifaximin will help decrease the amount of urea and ammonia reabsorbed in the intestines, in patients with renal failure, dialysis is imperative to recovery. After only one treatment with dialysis, the cognitive improvement is profound. As the acute kidney injury resolves, dialysis is no longer necessary.

It is unclear whether antiepileptics can also help with delirium. Valproic acid may inhibit glutamates action on the NMDA receptor. Glutamate mediated neuronal excitotoxicity has been postulated as a cause of nerve cell death. Antiepileptics may be beneficial at attenuating the deleterious effects of glutamate in the brain.

Delirium can also be caused by too much serotonin. Medications such as serotonin re-uptake inhibitors (SSRIs), linezolid, metoclopramide, fentanyl and baclofen can cause the serotonin syndrome. Patients typically exhibit some type of clonus (12). We recommend stopping all antidepressants in critically ill patients exhibiting signs of delirium. After the delirium subsides, resuming the SSRI appears appropriate. Depression is common as patients recover from their critical illness and the addition of an SSRI may be beneficial prior to transfer out of the intensive care unit.

By adhering to the above recommendations, you will be able to recognize delirium and institute effective lifesaving treatments. Patients and their family members will be grateful as they will be able to communicate with their loved ones once again. Nurses will also be happier as they will suffer less emotional and physical trauma. This will lead to a faster patient recovery and a shorter length of hospitalization.

References

1. Yamaguchi T, Tsukioka E, Kishi Y. Outcomes after delirium in a Japanese intensive care unit. Gen Hosp Psychiatry. 2014;36(6):634-6. [CrossRef] [PubMed]
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Reference as: Schmitz ED, Vu JB. Brief review: delirium. Southwest J Pulm Crit Care. 2014;9(6):343-7. doi: http://dx.doi.org/10.13175/swjpcc166-14 PDF

December 2013 Critical Care Case of the Month: I Don’t Have a Drinking Problem

Robert Raschke MD

Elijah Poulos MD

Adam Bosak MD

Critical Care Medicine

Banner Good Samaritan Medical Center

Phoenix, AZ

History of Present Illness

A 69-year-old male retired diabetic police officer was admitted to the ICU with intractable vomiting, severe abdominal pain and acute blindness. About a week prior, he suffered urinary frequency and was prescribed ciprofloxacin at urgent care with a presumptive diagnosis of urinary tract infection.  Over the course of the week his urinary frequency resolved and he became anuric, he developed progressively worsening nausea and eventually vomiting to the point that he was unable to keep anything down, and severe bilateral lower abdominal and pelvic pain.    His wife and son actually forced him into the ER when he became blind the day of admission. He denied fever, dysuria, cough and headache.   In our emergency room he was noted to be in moderate distress with tachycardia, tachypnea, hyperpnoea and completely blind in both eyes unable to discern even simple shadows.

PMH, SH, FH

The patient is a retired police officer with a past medical history of diabetes mellitus and benign prostatic hypertrophy.  The patient denied alcohol, tobacco, or illicit drug use. He works out at a local gym almost daily since being diagnosed with diabetes a couple of years ago.

Medications

• Glipizide
• Metformin
• Tamsulosin

Physical Exam

Blood pressure160/95 mmHg with a heart rate of 110, respiratory rate 35, SpO2 99% on 2 lpm nasal cannula, and temp 36.0° C.  He appeared uncomfortable and moderately distressed, lethargic but arousable with GCS 13. He was able to briefly answer simple questions. His eyes were conjugate, but did not track nor fix on objects placed in front of his eyes, and he could vaguely discern the light of a bright flashlight shined into both eyes. His pupils were 3-4 mm and fixed, with no light reflex elicitable, even with magnified examination of the pupil using an ophthalmoscope.  On fundoscopic exam his discs were flat, and there were no hemorrhages or other lesions seen.  He was tachycardic but regular with normal heart tones, and a bedside echocardiogram showed good left ventricular function.  He had Kussmaul breathing with an odor of ketones and clear lungs. The lower abdomen was distended and tender, and a Foley catheter insertion returned 2 liters of yellow urine which resolved his abdominal pains.  He had no peripheral edema and his hands were cool.  The rest of his physical examination was unremarkable.

Laboratory Evaluation

Initial laboratory evaluation included a white blood count 24.3 K/mm3 with 79% segmented neutrophils and no bands, hemoglobin 14.7 g/dL; sodium 138 mmol/L;  potassium 5.1 mmol/L; chloride 92 mmol/L; and CO₂ 4 mmol/L, yielding an anion gap of 44 when corrected.  His BUN was 116 mg/dL; creatinine of 7.7 mg/dL.  A venous blood gas showed a pH 6.77 pCO₂ 17 mmHg; pO₂ 73 mmHg; bicarbonate of 3 mmol/L. Urinalysis showed negative leukocyte esterase, 1-5 leukocytes per HPF, glycosuria and ketonuria.

Radiology Evaluation

Admission chest x-ray is in Figure 1. 

Figure 1. Admitting chest radiograph.

Computerized tomography of the abdomen showed no urinary tract obstruction (was performed after the Foley catheter was placed) and no other significant findings. Piperacillin/tazobactam and gentamicin were started for possible urinary tract infection with sepsis.

Which of the following is the best fits the clinical presentation explaining both his metabolic abnormalities and blindness? (click on correct answer to move to next panel)

1. Acute renal failure
2. Alcoholic ketoacidosis
3. Diabetic ketoacidosis
4. Ethylene glycol ingestion
5. Methanol ingestion

Reference as: Raschke RA, Poulos E, Bosak A. December 2013 critical care case of the month: I don't have a drinking problem. Southwest J Pulm Crit Care. 2013;7(6):328-35. doi: http://dx.doi.org/10.13175/swjpcc141-13 PDF