Night between 6/8/22 and 6/9/22
N.V. was admitted through ER with abnormal bruising, chest pain, vomiting, pallor, palpitations, splenomegaly, recent weight loss (26 lbs).
On exam HR 118, scattered petechiae and bruising across the torso, arms and legs, and bilateral conjunctive and scleral hemorrhages.
ER work up included CT head (normal) and EKG (sinus tach).
Coagulation profile showed elevated PT (13.4), INR (1.14) and D-dimer (729), but normal fibrinogen and aPTT.
CBC revealed severe thrombocytopenia and anemia. WBC 4.52, Hgb 8.1, Hct 23.3, high RDW (19.3), low Platelets (11), low Neutrophils (15), and low Lymphocytes (40.0).
Other relevant labs: low potassium (3.4), low chloride (97), high Anion Gap (14), high AST (140), high Uric Acid (13.7), and high LDH (1890).
Dr. J.C. ordered malignancy workup, Rasburicase, and platelet infusions.
His impression was acute pancytopenia with predominantly severe thrombocytopenia, blasts concerning for malignancy and tumor lysis syndrome.
Subsequently, arrangements were made for N.V.’s admission to hematology/oncology on Dr. G’s service for suspected malignancy.
N.V. was started on Allopurinol and Rasburicase to treat elvated uric acid in the suspected setting of tumor lysis syndrome. Allopurinol 200 mg x 4 and Rasburicase 9 mg x 1 were given to N.V. over the next 48 hours.
N.V. was transfused 1 unit platelets.
BMP were repeated twice on 6/9/22 and showed minor changes, but rising LDH (2065 at 7:43 PM).
6/10/22
N.V. had an episode of coughing up small amounts of blood overnight, was experiencing labored breathing, and O2 Sat was 88 on RA. The CXR showed “overinflated lungs”; Xopenex was given.
At 12:29 AM, CBC with differential showed WBC within the normal range (6.83); Hgb 7.1, Hct 21.1, high RDW (19.8), low platelets (43), and low Neutrophils (12.0).
BMP at 3:32 AM showed low creatinine (0.66), low Uric Acid (<1.0), and high LDH (2484).
N.V. was clinically diagnosed with B-Cell Acute Lymphoblastic Leukemia (ALL) at 12:19 PM.
A plan was made for surgery for port placement, and lumbar puncture (LP) with intrathecal (IT) Cytarabine (it is unclear whether Cytarabine was part of a clinical trial).
His pre-surgery platelet goal was 80; however, it is clear that goal was not attained prior to the operation. 2 units platelets were given prior to surgery and three units platelets and 1 unit pRBCs were given during the operation. Moreover, 1 unit pRBCs was given during the procedure. Surgery started at 2:55 PM and ended at 5:58 PM.
Drs. M.A. and A.L. performed the insertion of a right subclavian port during the operation. Multiple attempts to cannulate the left subclavian vein were unsuccessful; therefore, the right subclavian vein was cannulated and a wire was fed into the right atrium under fluoroscopic guidance. M.A. noted that “this was actually more difficult than expected.” The dilator and introducer were fed over the wire into the right atrium. The catheter was fed through the introducer; however, according to M.A., “it was seen to be quite long”, so they then removed it, leaving the introducer in, cut roughly 3 cm off, and placed it back in and progressed it to the right atrium. Postoperative chest x-ray showed that the catheter was still “a little bit long”.
Drs. K.P. and L.P. performed an intrathecal catheter placement, IT cytarabine infusion, and bone marrow biopsy. After the IT catheter placement, the patient was administered Cytarabine 70mg. The bone marrow biopsy also required the needle to be introduced twice in order to obtain the necessary sample from the iliac crest.
Upon return from the OR, in the PACU, the patient was pale, with shortness of breath, and active bleeding from the BMA site. pRBC and platelets were ordered. Platelet transfusion began prior to PACU transfer.
N.V. was transported to the PACU at 6:01 PM where he experienced tachypnea and coffee ground emesis. BMP was notable for hyperkalemia. The patient had pitting edema and crackles on lung exam that were concerning for fluid overload in the setting of multiple blood transfusions. Lasix was given. Vital signs taken in the PACU at 6:07 PM showed a respiratory rate of 44, diastolic blood pressure at 57, and SpO2 was 93%.
At 6:15 PM, respiratory rate decreased to 31 and his diastolic blood pressure was at 49.
CBC with differential at 6:22 PM exhibited high WBC (16.56), low RBC (2.63), low Hgb (7.3), low Hct (22.9), low MCHC (31.9), low RDW (20.0), low platelets (88), low Neutrophils (11.0), low Lymphocytes (39.0).
At 6:30, RR 35 and diastolic BP increased to 63.
At 7:00 PM, RR 33 and diastolic BP was 45.
At 7:30 PM, RR: 23; diastolic BP: 61.
At 7:45 PM, HR 116, RR 28, and diastolic BP was 48.
Arterial blood gases were not performed while he was in the PACU.
At 8:00 PM the patient was discharged from the PACU and transferred to the step-down floor.
On the step-down unit, his course was marked by progressively worsening respiratory distress over 4 hours. During that time, the following occurred:
At 9:15 PM, peripheral pulse rate was 120, respiratory rate was 34, systolic BP was 98, and diastolic BP was 57.
At 10:32 PM, ABG results were remarkable for acidosis (pH 7.21), low PO2 (65). low PCO2 (<19), elevated carboxyhemoglobin (2.2), total hemoglobin 8.4, and elevated lactate (16.0!).
At 11:00 PM, peripheral pulse rate was 123, respiratory rate was 46, and BP was 118/58.
At 11:16 PM, ABGs showed pH increased to a normal range (7.35) while pCO2 remained low (22), PO2 was low (<34), Bicarbonate was low (12.1), base excess was low (-11.41), total hemoglobin was low (7.7), and lactate remained the same (i.e., very high, >16!).
The last CBC at 11:23 PM, taken before N.V.’s death, showed that WBC was high (15.25), RBC was low (2.60), Hgb was low (7.4), Hct was low (22.8), RDW was high (20.2), platelets were low (73), Neutrophils were low (18), and Lymphocytes were low (34.0).
Vitals at 11:30 showed heart rate high at 118-120, respiratory rate decreased to 24, and diastolic BP was low at 55.
At 11:45 PM, heart rate was 132-133, respiratory rate was 41, diastolic BP was 115, and MAP was at 121.
Shortness of breath worsened; the “rapid response” team was called to the floor at this time. N.V. was subsequently transported to the PICU at or about 12:00 AM (midnight).
6/11/22
In the PICU it was planned that the patient would start on BIPAP due to increased work of breathing, NS Bolus (due to widened pulse pressure). Ceftriaxone and vancomycin were ordered. Ceftriaxone was given while vancomycin was not due to the following events:
Due to N.V.’s worsening respiratory distress, the decision was made to intubate. Immediately after intubation, he exhibited “PVCs” which then transitioned to V-tach. CPR was initiated.
During the code, echocardiogram did not see cardiac tamponade. Ultrasound did not show pnuemothoraces. Heart rhythm remained PEA/pulseless without ROSC despite multiple rounds of epinephrine. Approximately one hour after cardiac arrest, N.V.’s pupils were noted to be fixed and nonreactive. N.V. was declared dead.
In the PICU note, the reason of death was listed as distributive shock secondary to sepsis secondary to ALL.
According to ped heme/onc attending’s progress note (prepared 12 hours post-death), potential causes of death did not include tumor lysis syndrome but consisted of massive pulmonary embolism, intracranial hemorrhage, sepsis-septic shock, and volume overload.
Details of the autopsy report are uploaded as a separate file.
However, the examiner’s opinion was that N.V.’s death was the result of acute tumor lysis with acute kidney injury and pulmonary microvascular coagulopathy due to cytostatic induction therapy for B-cell type acute lymphoblastic leukemia.
The questions raised by this case are as follows:
1. Should the treatment team have delayed the procedures until thrombocytopenia addressed?
2. Should the treatment team have performed ABGs, CT PE protocol in the PACU given the shortness of breath and tachypnea?
3. Should the treatment team have transferred earlier the patient to the PICU (maybe directly from the PACU) given the post-op deterioration?
4. Was there a failure to timely diagnose respiratory complications of TLS, i.e., pulmonary microvascular coagulopathy (i.e., pulmonary micro-thrombi)?
5. Was there a failure to properly treat tumor lysis syndrome?
6. Was there a failure to timely and properly diagnose and treat acute kidney injury secondary to tumor lysis syndrome?
7. Was there a failure to timely and properly diagnose and treat sepsis?
8. What is the cause of death for this unfortunate teenage male patient? Tumor lysis syndrome (medical examiner’s conclusion)? Sepsis (some treating physicians’ differential)? Combined TLS / sepsis?
9. Assuming any of the foregoing departures from proper practice, did such departures cause or contribute to this patient’s death?
Files:
Q: Is it possible to review all labs including complete BMP and CMP , urine studies and chest X-ray and coagulation studies ?
A: —
Q: I would be happy to respond as a pediatric heme/onc but unfortunately the platform is not allowing me to do so at present.
A: —
Do you believe there might have been medical error?
In my opinion, this patient did not die of tumor lysis syndrome. He died of acute lymphoblastic leukemia complicated by sepsis. This was also complicated by volume overload. There are two potential medical errors here. They both involve judgement more than a violation of the standard of care. 1) Antibiotics appear to have been administered about 48 hours too late. Very early in the course of the patient's treatment, malignancy was suspected and tumor lysis syndrome was treated. The patient was given Rasburicase and allopurinol and his second uric acid level was very low and the creatinine and potassium were normal. TLS was adequately treated and not a problem. However, in the description above, antibiotics were not mentioned until the patient was dying in the PICU in the early hours of 6/11. Ceftraixone was given, but he died before receiving the vancomycin. It would take a careful review to see if antibiotics were not given earlier. Fever is not mention and the patient did not have absolute neutropenia. He also did not have an elevated white blood count at first and this may have caused some of the physicians to think he did not have infection. However, ALL is a stem cell disorder and one can not assume that his neutrophils and the rest of his immune system that involves a complex interplay between the neutrophils and lymphocytes, natural killer cells, monocytes, macrophages, dendritic cells is working properly. If a patient with untreated ALL is sick at all, he needs antibiotics. 2) Patients with acute leukemia need primary treatment as soon as possible. The team was perhaps mislead by the patient's normal white blood cell early on. This was an unusual and sneaky leukemia in that the WBC was not very elevated and yet there was very extensive infiltration of multiple organs at the time of the autopsy 48 hours later. The received some empiric treatment before the marrow results could have been obtained (12 noon on 6/10, meaning the diagnosis was made by evaluation of the peripheral blood. The clinical team could have pushed the pathology department to give their best diagnosis based on the peripheral blood analysis on the 9th. The patient could have been given a bedside PICC line and and a marrow done at the bedside and systemic chemotherapy given later that day. The trip to the OR for a port and a bone marrow biopsy and lumbar puncture was, at least in retrospect, a waste of time. With this approach, the patient might have survived.
Do you believe there might have been causation (i.e. the medical error resulted in an injury)?
See above for details. Even with early antibiotics and early chemotherapy, this patient still could easily have died. He was critically ill when he came to the emergency room and he had a very aggressive tumor with extensive invasion of multiple organs.
What makes you a good expert for this case?
I have trained or practiced at 3 major medical centers in the country. I have been in practice for 30 years, including a time when I was younger and took care of many critically ill patients in the ICU, CCU, bone marrow transplant and leukemia services. I have actually done many central line placements, lumbar punctures, and bone marrow biopsies myself, i.e. I have been down in the weeks. I have also treated patients with ALL and AML and many other hematologic malignancies.
How often do you encounter cases similar to this one in your practice?
Not so much anymore. I only have one ALL patient that I still follow - I treated him 15 years ago and he is cured. I now see only adults and we send our acute leukemic patients to the medical center. I have been in private practice since 1999.
Do you believe there might have been medical error?
Patient had ALL I needed acute intervention. The procedure is to make the definitive diagnosis including bone marrow biopsy, as well as to start treatment as soon as possible, such as vascular access and bone marrow biopsy. We needed to be done as soon as possible, and they were. Supportive measures, such as platelet transfusion were given appropriately. Well, I am not an expert in intensive care, as a hematologist/oncologist, and after reviewing the autopsy, it appears he had widespread diffuse, ALL, infiltrating a number of organs. He likely did have tumor, lysis syndrome, but I believe he was treated appropriately with a spirit case to lower the uric acid, fluids, and ICU management. I would defer issues, such as work out for PE and management of things like DIC with pressers or other agents to intensivist opinions
Do you believe there might have been causation (i.e. the medical error resulted in an injury)?
See above. Patient came in acutely ill, with diffuse, infiltration of acute leukemia. I think appropriate measures were performed. Patient suffered, poor outcome, mainly because of biology of the disease.
What makes you a good expert for this case?
I am adult hematologist/oncologist. I do see patients with acute leukemia’s, but seldom do I see 15 year olds.
How often do you encounter cases similar to this one in your practice?
Patients with acute lymphoblastic leukemia usually are seen in our hospital one to two times a year. When they come in, they are almost always quite ill. I know that children with a Hill I’ll do better than adults with a LL, however, this patient was 15 years old, and I almost never see that age group.
Do you believe there might have been medical error?
The delay in getting an emergent hematology consultation .Did any physician look at the peripheral smear There likely was a delay in diagnosis in a critically ill patient who deteriorated rapidly.Probably transfer to a more acute floor such as an ICU earlier and more frequent labs , such as renal function, uric acid , LDH, coagulation studies etc Careful review f all records is required for a definitive opinion
Do you believe there might have been causation (i.e. the medical error resulted in an injury)?
ALL is a critical disease and tumor lysis syndrome can frequently be fatal Any dalay in diagnosi or treatment is likely a causative factor Ideally there would not habe been dalays and this could have altered the outcome .
What makes you a good expert for this case?
Expertise in hematologic malignancies and 40 plus years of treating them Extensive review of records and both experience for defense and plaintiffs including causation issues and failure to treat in a timely manner
How often do you encounter cases similar to this one in your practice?
fairly often but this isa very broad question
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